Behavioral Neuroscience of Drug Addiction (Current Topics in Behavioral Neurosciences)

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Current Topics in Behavioral Neurosciences Series Editors: Mark Geyer, La Jolla, CA, USA Bart Ellenbroek, Hamburg, Germany Charles Marsden, Nottingham, UK

About this series Current Topics in Behavioral Neurosciences provides critical and comprehensive discussions of the most significant areas of behavioral neuroscience research, written by leading international authorities. Each volume offers an informative and contemporary account of its subject, making it an unrivalled reference source. Titles in this series are available in both print and electronic formats. With the development of new methodologies for brain imaging, genetic and genomic analyses, molecular engineering of mutant animals, novel routes for drug delivery, and sophisticated cross-species behavioral assessments, it is now possible to study behavior relevant to psychiatric and neurological diseases and disorders on the physiological level. The Behavioral Neurosciences series focuses on ‘‘translational medicine’’ and cutting-edge technologies. Preclinical and clinical trials for the development of new diagnostics and therapeutics as well as prevention efforts are covered whenever possible.

David W. Self

l

Julie K. Staley

Editors

Behavioral Neuroscience of Drug Addiction

Editors Prof. Dr. David W. Self University of Texas Southwestern Medical Center Dept. Psychiatry 5323 Harry Hines Blvd. Dallas TX 75390-9070 USA [email protected]

Julie K. Staley{, Ph.D. Department of Psychiatry Yale University School of Medicine VACHS 116A2 950 Campell Ave. West Haven CT 06516 USA

ISSN 1866-3370 e-ISSN 1866-3389 ISBN 978-3-642-03000-0 e-ISBN 978-3-642-03001-7 DOI 10.1007/978-3-642-03001-7 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2009938007 # Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover illustration: Artistic representation of oscillatory synchrony and timing of neurons in networks by Gyorgy Buzsaki Cover design: WMXDesign GmbH, Heidelberg, Germany Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

Drug addiction is a chronically relapsing mental illness involving severe motivational disturbances and loss of behavioral control leading to personal devastation. The disorder afflicts millions of people, often co-occurring with other mental illnesses with enormous social and economic costs to society. Several decades of research have established that drugs of abuse hijack the brain’s natural reward substrates, and that chronic drug use causes aberrant alterations in these rewardprocessing systems. Such aberrations may be demonstrated at the cellular, neurotransmitter, and regional levels of information processing using either animal models or neuroimaging in humans following chronic drug exposure. Behaviorally, these neural aberrations manifest as exaggerated, altered or dysfunctional expression of learned behavioral responses related to the pursuit of drug rewards, or to environmental factors that precipitate craving and relapse during periods of drug withdrawal. Current research efforts are aimed at understanding the associative and causal relationships between these neurobiological and behavioral events, such that treatment options will ultimately employ therapeutic amelioration of neural deficits and restoration of normal brain processing to promote efforts to abstain from further drug use. The Behavioral Neuroscience of Drug Addiction, part of the Springer series on Current Topics in Behavioral Neurosciences, contains scholarly reviews by noted experts on multiple topics from both basic and clinical neuroscience fields. In the first two chapters, recent technological advances in the ability to monitor synaptic neuroplasticity and transient dopamine release events are discussed in relation to drug and alcohol addiction models. These studies have greatly advanced our understanding of how chronic drug exposure changes the responsiveness of primary reward substrates for drugs of abuse. Subsequent chapters illustrate how these events translate into addictive behavior and recruit additional brain regions involved in reward-related learning and behavioral disinhibition. Other chapters delve into the relationship between heightened drug responsivity and the propensity for relapse, and the neurobiology of anhedonia after chronic drug use is discontinued. Together, these chapters provide a focused and critical review of current animal models and methods along with functional relationships between v

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neurobiological and behavioral change. Many of the neurobiological and behavioral changes produced by chronic drug exposure in animals are reflected in human studies using modern neuroimaging and neurocognitive analyses, while others differ. The second part of the volume is dedicated to studies in human drug abusers, beginning with two chapters on alterations in drug and neurotransmitter receptor levels, dopamine release, and their relationship to drug taking and craving. In addition, the association of genomic markers with vulnerability to drug and alcohol addiction is reviewed in relation to genes known to be involved in transmitting drug signals and drug metabolism, and other approaches to identify novel genes associated with addicted phenotypes that could ultimately serve as targets for treatment. Three chapters discuss the various cognitive abnormalities that accompany drug addiction, including deficits in attention, memory, and executive control, susceptibility of the adolescent brain, and the impact of such changes on the inability to make appropriate and beneficial life choices in the context of a behavioral economic model of addiction. These latter chapters illustrate the global impact of druginduced alterations discussed in earlier chapters on complex neurocircuitry involved in the intricate interplay between cognitive processing and decisionmaking. Finally, while several non-pharmacological treatments for addiction have been explored, an explosion in potential pharmacological targets has lead to several novel treatments based on known and unknown mechanisms of action, and the latest findings are compared with more traditional approaches. The findings reviewed in this volume suggest that an emerging consensus exists for the underlying pathology of drug addiction. Basic neuroscience research conducted in animal models suggests that neuroadaptations in limbic brain regions promote drug-taking behavior by enhancing the neural substrates of primary drug reward, while weakening neural mechanisms of inhibitory control. The latter is paralleled in humans by deficits in neocortical function and executive/cognitive information processing. However, human neuroimaging studies also suggest that drug addiction is associated with deficits in dopaminergic neurotransmission, the major neural substrate for primary drug reward. These and other discrepancies indicate that more work is needed to reconcile the findings from animal models and human drug addiction. Furthermore, there are numerous other drug-induced changes that encompass regulation of gene expression, intracellular signaling molecules, and several other neurotransmitter, metabolic and morphological changes that have been identified, but their relevance to human behavioral change is unknown. Ultimately, it is important for animal models to better emulate human cognitive abnormalities so that critical cause-effect relationships between neurobiological and behavioral change may be determined. We hope the breadth of behavioral neuroscience endeavor contained in this volume will assist in directing future research aimed at integrating human and animal work towards a cohesive body of research with substantial implications for treatment. Dallas, TX West Haven, CT

David W. Self Julie K. Staley{

Dedication Dr. Julie Staley passed away on July 25, 2009 shortly after completing her work as co-editor for this book. Her struggle with a long-term illness never once diminished her devotion and vigor for scientific endeavor, and her profound dedication to this project. This book is dedicated to Julie, and the tireless enthusiasm she displayed in life remains an inspiration for all of us. Dr. Julie Staley

David Self

Kelly Cosgrove

Contents

Part I Preclinical Neuroscience Neuroplastic Alterations in the Limbic System Following Cocaine or Alcohol Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Garret D. Stuber, F. Woodward Hopf, Kay M. Tye, Billy T. Chen, and Antonello Bonci Dopamine Signaling in the Nucleus Accumbens of Animals Self-Administering Drugs of Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Ingo Willuhn, Matthew J. Wanat, Jeremy J. Clark, and Paul E.M. Phillips Amygdala Mechanisms of Pavlovian Psychostimulant Conditioning and Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Deanne M. Buffalari and Ronald E. See Prefrontal Cortical Regulation of Drug Seeking in Animal Models of Drug Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Heather C. Lasseter, Xiaohu Xie, Donna R. Ramirez, and Rita A. Fuchs Neural Substrates of Psychostimulant Withdrawal-Induced Anhedonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Manoranjan S. D’Souza and Athina Markou Sensitization Processes in Drug Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Louk J.M.J. Vanderschuren and R. Christopher Pierce Part II Clinical Neuroscience Imaging Receptor Changes in Human Drug Abusers . . . . . . . . . . . . . . . . . . . . . . 199 Kelly P. Cosgrove

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Imaging Neurotransmitter Release by Drugs of Abuse . . . . . . . . . . . . . . . . . . . . 219 Diana Martinez and Rajesh Narendran Imaging Cognitive Deficits in Drug Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Thomas Lundqvist Neural Markers of Genetic Vulnerability to Drug Addiction . . . . . . . . . . . . . 277 Daniel J. Mu¨ller, Olga Likhodi, and Andreas Heinz The Role of Executive Control in Human Drug Addiction . . . . . . . . . . . . . . . . 301 Robert Hester, Dan I. Lubman, and Murat Yu¨cel The Behavioral Economics of Drug Dependence: Towards the Consilience of Economics and Behavioral Neuroscience . . . . . . . . . . . . . . . . . . . 319 Warren K. Bickel, Richard Yi, E. Terry Mueller, Bryan A. Jones, and Darren R. Christensen Novel Pharmacological Approaches to Drug Abuse Treatment . . . . . . . . . . . 343 Ellen Edens, Alfredo Massa and Ismene Petrakis Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

Contributors

Warren K. Bickel Departments of Psychiatry and Radiology, Center for Addiction Research, University of Arkansas for Medical Sciences, 4301 W. Markham # 554, Little Rock, AR 72205, USA, [email protected] Antonello Bonci Ernest Gallo Clinic and Research Center, University of California San Francisco, 5858 Horton Street, Emeryville, CA 94608, USA, [email protected] Deanne M. Buffalari Department of Neuroscience, Medical University of South Carolina, BSB 416 173 Ashley Avenue, Charleston, SC 29425, USA Billy T. Chen Ernest Gallo Clinic and Research Center, University of California San Francisco, 5858 Horton Street, Emeryville, CA 94608, USA Anna Rose Childress Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, [email protected] Jeremy J. Clark Department of Psychiatry and Behavioral Science, University of Washington, Box 356560, Seattle WA 98195-6560, USA Kelly Cosgrove Departments of Psychiatry, Yale University School of Medicine & VACHS 116A6, 950 Campbell Avenue, West Haven, CT 06516, USA, [email protected]

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Manoranjan S. D’Souza Department of Psychiatry M/C-0603, University of California, 9500 Gilman Drive, La Jolla CA 92093-0603, USA Rita Fuchs Department of Psychology, University of North Carolina, CB #3270, Davie Hall, Chapel Hill, NC 27599-3270, USA, [email protected] Andreas Heinz Clinic for Psychiatry and Psychotherapy, Charite´ University Medicine, Campus Charite´–Mitte, Schumannstraße 20/21, 10117 Berlin, Germany, andreas.heinz@ charite.de F. Woodward Hopf Ernest Gallo Clinic and Research Center, University of California San Francisco, 5858 Horton Street, Emeryville, CA 94608, USA Heather C. Lasseter Department of Psychology, University of North Carolina, CB #3270, Davie Hall, Chapel Hill, NC 27599-3270, USA Daniel Lubman Department of Psychiatry, ORYGEN Research Centre, The University of Melbourne, Victoria, Australia and Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne, Melbourne, Victoria, Australia, [email protected] Thomas Lundqvist Drug Addiction Treatment Centre, Lund University Hospital, 221 85 Lund, Sweden, [email protected] Athina Markou Department of Psychiatry M/C-0603, University of California, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA, [email protected] Diana Martinez NYS Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA, [email protected] Wilbur D. Mills University of Arkansas for Medical Sciences, Departments of Psychiatry and Radiology, Center for Addiction Research, 4301 W. Markham # 554, Little Rock, AR 72205, USA

Contributors

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Ismene Petrakis Yale University School of Medicine, VA Connecticut Healthcare System, 950 Campbell Avenue #116A, West Haven, CT 06516, USA, [email protected] Paul E.M. Phillips Department of Psychiatry and Behavioral Science, University of Washington, Box 356560, Seattle WA 98195-6560, USA, [email protected] R. Christopher Pierce Department of Pharmacology and Anatomy, The Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands Donna R. Ramirez Department of Psychology, University of North Carolina, CB #3270, Davie Hall, Chapel Hill, NC 27599-3270, USA Ronald E. See Department of Neuroscience, Medical University of South Carolina, BSB 416 173 Ashley Avenue, Charleston, SC 29425, USA, [email protected] Garret D. Stuber Ernest Gallo Clinic and Research Center, University of California San Francisco, 5858 Horton Street, Emeryville, CA 94608, USA Kay M. Tye Ernest Gallo Clinic and Research Center, University of California San Francisco, 5858 Horton Street, Emeryville, CA 94608, USA Louk Vanderschuren Department of Pharmacology and Anatomy, The Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584-CG Utrecht, The Netherlands, [email protected] Matthew J. Wanat Department of Psychiatry & Behavioral Science, University of Washington, Box 356560, Seattle WA 98195-6560, USA Ingo Willuhn Department of Psychiatry & Behavioral Science, University of Washington, Box 356560, Seattle WA 98195-6560, USA Xiaohu Xie Donna R. Ramirez, Department of Psychology, University of North Carolina, CB #3270, Davie Hall, Chapel Hill, NC 27599-3270, USA

Neuroplastic Alterations in the Limbic System Following Cocaine or Alcohol Exposure Garret D. Stuber, F. Woodward Hopf, Kay M. Tye, Billy T. Chen, and Antonello Bonci

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2 Ionotropic Glutamate Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3 Cocaine-Induced Synaptic Plasticity in Midbrain DA Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4 Cocaine-Induced Synaptic Plasticity in the NAc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5 Amygdala Plasticity and Drugs of Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 6 Alcohol and Plasticity in Glutamate Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 7 Altered Intrinsic Excitability After Alcohol or Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 8 Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Abstract Neuroplastic changes in the CNS are thought to be a fundamental component of learning and memory. While pioneering studies in the hippocampus and cerebellum have detailed many of the basic mechanisms that can lead to alterations in synaptic transmission based on previous activity, only more recently has synaptic plasticity been monitored after behavioral manipulation or drug exposure. In this chapter, we review evidence that drugs of abuse are powerful modulators of synaptic plasticity. Both the dopaminergic neurons of the ventral tegmental area as well medium spiny neurons in nucleus accumbens show enhanced excitatory synaptic strength following passive or active exposure to drugs such as cocaine and alcohol. In the VTA, both the enhancement of excitatory synaptic strength and the acquisition of drug-related behaviors depend on signaling through the N-methyl-D-aspartate receptors (NMDARs) which are mechanistically thought to lead to increased synaptic insertion of a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptors (AMPARs). Synaptic insertion of AMPARs by drugs of abuse can be long lasting, depending on the route of administration, G.D. Stuber, F.W. Hopf, K.M. Tye, B.T. Chen and A. Bonci (*) Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, CA, USA e-mail: [email protected]

D.W. Self and J.K. Staley (eds.), Behavioral Neuroscience of Drug Addiction, Current Topics in Behavioral Neurosciences 3, DOI 10.1007/7854_2009_23, # Springer‐Verlag Berlin Heidelberg 2009, published online 15 September 2009

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number of drug exposures, or whether the drugs are received passively or selfadministered. Keywords Plasticity Dopamine Glutamate Accumbens Ventral tegmental area Amygdala Drug abuse Reward

1 Introduction The mesolimbic dopamine (DA) system, formed in part by the ventral tegmental area (VTA) and nucleus accumbens (NAc), is an integral part of the brain’s natural reward circuit. The VTA is a major source of DA for brain circuits involved in encoding of reinforcement and learning, and the NAc is a critical node that integrates limbic and motivational input (including DA signals from the VTA) to influence behavioral output. Thus, these brain regions, in concert with other areas such as the prefrontal cortex, thalamus, and amygdala, are considered to play a critical role in the control of motivated and goal-directed behaviors, including the development and expression of addictive behavior (Cardinal et al. 2002; Epstein et al. 2006; Kalivas and McFarland 2003; Mogenson et al. 1980). In addition, recent studies suggest that addiction is a form of maladaptive learning, where aberrant neural links are formed between the action of taking drugs and the “reward” or alleviation of withdrawal-related negative states produced by the drugs (Hyman et al. 2006). For this reason, this chapter will briefly address the consequences of passive versus active exposure to drugs. Repeated passive exposure to a given drug can enhance or “sensitize” the locomotor-activating effects of that drug (for review, see Robinson and Berridge 1993). Since locomotor sensitization can be long-lasting and can enhance subsequent drug self-administration, sensitization has been considered a model of enhanced drug seeking during abstinence. However, although pharmacological effects through passive drug exposure can produce enduring plastic changes, human drug intake is typically active and voluntary, and associative learning between such volitional drug taking and the positive or negative reinforcing consequences may be a critical component in the development of addiction. Overall, this chapter seeks to address the hypothesis that drugs of abuse produce persistent changes in neuronal function that may drive drug seeking following periods of abstinence. The ability of drugs to alter neuronal function was originally investigated predominantly through biochemical methods such as Western Blot, which allows one to determine changes in protein levels or phosphorylation state of a given receptor or channel subunit. More recently, large-scale screening for changes in protein levels (using proteomics) or mRNA levels (using DNA microarrays) have shown great promise for indicating potential changes in receptor or channel function. Importantly, ex vivo electrophysiological techniques in brain slice have

Neuroplastic Alterations in the Limbic System Following Cocaine or Alcohol Exposure

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allowed direct examination of functional changes in excitatory synaptic strength or ion channel activity after drug exposure. Electrophysiological studies are particularly critical because they provide detailed information about the functional state of a given receptor or channel, which can occur without concurrent alterations in total protein or mRNA in brain tissue. Thus, we will examine evidence that abused substances can cause long-term changes (after one day or more of withdrawal) in glutamate receptor and ion channel function in the VTA and NAc. While many other brain regions such as the prefrontal cortex play a very important role in drugdependent behaviors (Kalivas et al. 2005), those brain regions will not be addressed here. Furthermore, we will focus here on cocaine and alcohol, although many interesting studies have also been performed in relation to other abused drugs such as morphine, nicotine, and amphetamine.

2 Ionotropic Glutamate Receptors Ionotropic glutamate receptors are generally categorized into one of two distinct classes. Activation of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) by glutamate leads to fast onset/fast offset depolarization, which contributes to action potential induction in many cells (Bredt and Nicoll 2003). In contrast, N-methyl-D-aspartate receptors (NMDARs) have slower kinetics and are voltage-activated. That is, at resting membrane potentials they are blocked by Mg2+ and no current can pass. However, as the neuron becomes more depolarized, the Mg2+ block is alleviated, which allows for the passage of cations including Ca2+ when glutamate is bound to the receptor. Therefore, currents through the NMDAR both depolarize the neuron and elevate intracellular Ca2+, which is critical for induction of many enduring forms of synaptic plasticity. AMPARs are hetero or homomeric complexes composed of four subunit proteins (GluR1-4) (Hollmann and Heinemann 1994). In many brain regions including both the VTA and NAc, AMPARs are thought to exist as heteromeric complexes containing both GluR2/3 and GluR1 subunits in a basal state (Liu and Zukin 2007). At some synapses neuroplastic changes in AMPAR function are associated with the synaptic insertion of GluR1 subunits that form homomeric receptors lacking GluR2/3 (Bellone and Lu¨scher 2006; Plant et al. 2006). The formation and insertion of GluR2/3-lacking (GluR1 homomeric) receptors is of particular importance as these receptors pass more current while hyperpolarized at resting membrane potentials compared to when they are depolarized (rectification) as well be being permeable to Ca2+, which can facilitate further Ca2+-dependent changes in plasticity. To investigate the functional consequence of changes in GluR subunit composition of AMPARs, several compounds that are capable of selectively blocking GluR2-lacking AMPARs, such as 1-naphthylacetylsperimine (Naspm), Joro spider toxin, or philanthotoxin-7,4, have been used (Argilli et al. 2008; Conrad et al. 2008; Nilsen and England 2007).

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3 Cocaine-Induced Synaptic Plasticity in Midbrain DA Neurons There is a large body of literature demonstrating a role of DAergic transmission in learning and reinforcement (for reviews see Kelley 2004; Salamone et al. 2005; Schultz and Dickinson 2000; Wise 2004). Midbrain DA neurons exhibit bimodal firing rates (2–7 Hz tonic; 10–30 Hz Bursting) (Freeman and Bunney 1987; Schultz 1998). Tonic firing is hypothesized to lead to ambient, low levels of DA (~20 nM) capable of activating high affinity D2 receptors, while burst firing is hypothesized to cause transient surges in DA concentrations (>100 nM), which would be able to act on lower affinity D1 receptors (Missale et al. 1998). Burst firing of DA neurons in particular seems to be of distinct importance as cues that are associated with reward, which can serve to initiate goal-directed behavior, lead to phasic DA release after cue-reward learning (Phillips et al. 2003; Stuber et al. 2005). Thus, phasic activation of midbrain DA neurons is thought to promote goal-directed behavior, especially in relation to reward-predictive stimuli. Importantly, glutamatergic signaling potently modulates DAergic neuronal activity. Ionotropic glutamate receptor agonists can potently increase firing rates of DAergic neurons in vivo (Chergui et al. 1993; Grace and Bunney 1984; Johnson et al. 1992; Murase et al. 1993), while ionotropic antagonists attenuate firing (Charlety et al. 1991; Chergui et al. 1993). Furthermore, modeling studies predict that changes in AMPAR number or function should lead to profound alterations in the firing pattern of DA neurons, perhaps by indirectly inducing NMDAR activity which could lead to burst firing (Canavier and Landry 2006). Consistent with this notion, synapses onto DA neurons are highly plastic, exhibiting NMDARdependent long-term potentiation (LTP) (Liu et al. 2005; Ungless et al. 2001) and long-term depression (LTD) (Bonci and Williams 1996), as well as short-term plasticity involving changes in the amount or function of synaptic AMPA receptors (Bonci and Malenka 1999). Thus, it is hypothesized that such plasticity could modify AMPAR responses during environmental events that increase glutamate release onto DA neurons, and significantly alter the firing of DA neurons during goal-directed behavior. Indeed, nonassociative learning in relation to behavioral sensitization to cocaine, and cocaine- and morphine-induced conditioned place preference, are both blocked by VTA NMDAR antagonists (Harris and AstonJones 2003; Harris et al. 2004; Kalivas and Alesdatter 1993). Ungless et al. (2001) were the first to report that the ratio of AMPAR-mediated current to NMDAR-mediated current (termed the AMPAR/NMDAR ratio) is significantly elevated at excitatory synapses in the VTA relative to saline-injected controls 24 h after a single exposure to cocaine. The increase in the AMPAR/ NMDAR current ratio after cocaine exposure occludes further potentiation and induction of LTP, suggesting that these synapses already exist in an LTP-like state. Importantly, LTP of VTA glutamatergic synapses is observed after a single exposure to many other drugs of abuse, demonstrating a convergence of cellular responses within the VTA by all abused drugs (Saal et al. 2003). The mechanism underlying LTP of excitatory synapses onto VTA DA neurons appears to be


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mediated by the initial insertion of GluR2-lacking AMPARs (Bellone and Lu¨scher 2006; Lu¨scher and Bellone 2008; Mameli et al. 2007). This insertion of new GluR2-lacking AMPAR subunits is thought to be transient, so that the homomeric GluR1 AMPA receptors are eventually replaced by newly synthesized GluR2/3 after many hours. Furthermore, the insertion of GluR2-lacking AMPARs can be reversed by activation of the metabotropic glutamate receptor (mGluR) mGluR1, which induces replacement of GluR2-lacking receptors with GluR2-containing receptors. This is hypothesized to readjust synaptic strength back to basal levels and therefore prevent behavioral changes that could contribute to development of addiction. Thus, LTP observed in VTA DA neurons after a single cocaine exposure is transient, exhibiting potentiated AMPAR currents 5 but not 10 days later (Ungless et al. 2001). The same time course for potentiated VTA AMPAR currents has also been observed following repeated cocaine injections (Borgland et al. 2004), suggesting that increased cocaine exposure does not increase the duration of the VTA AMPAR enhancement. It also is interesting that a single cocaine injection produces changes in opiate conditioned place preference and aversion with a similar time course (altered conditioning 5 but not 10 days after cocaine exposure), and these effects of cocaine were prevented by inhibition of NMDARs in the VTA during cocaine exposure (Kim et al. 2004). These studies suggest that many forms of LTP require Ca2+ influx through NMDARs, and enhanced AMPAR number or signaling in the VTA following cocaine exposure could act to facilitate DA-mediated learning. Consistent with this hypothesis, establishment of place preference for both cocaine and morphine depends on NMDAR signaling (Harris and Aston-Jones 2003; Harris et al. 2004), as does conditioned approach behavior to cues that predict natural rewards (Stuber et al. 2008b). Reinstatement of cocaine-seeking behavior (either by electrical stimulation or by cocaine priming) following cessation of self-administration also is blocked by intra-VTA glutamate antagonism (Sun et al. 2005; Vorel et al. 2001). Pathological drug use is thought to highjack natural associative learning mechanisms in order to facilitate and exacerbate drug-seeking behavior (Hyman et al. 2006; Kelley 2004). Since the process of active drug-seeking behavior is very different from passive experimenter-delivered drug exposure, it is critical to investigate changes in synaptic plasticity in the VTA following voluntary drug-self administration. Chen and colleagues (2008) found that voluntary cocaine self-administration in rats increased excitatory synaptic strength in VTA DA neurons for up to 3 months following cessation of chronic self-administration, in stark contrast to passive involuntary cocaine administration that potentiates excitatory synaptic strength for ~1 week as described above. Interestingly, yoked rats that received the same amount and temporal pattern of involuntary cocaine did not show an increase in synaptic strength. Finally Changes in VTA NMDAR levels have also been observed during cocaine withdrawal (Lu et al. 2003; Hemby et al. 2005), although electrophysiological studies have not been performed to corroborate these results. Taken together, these data suggest that a number of behavioral conditions can produce short-term plasticity in the VTA (passive cocaine exposure, self-administration of natural reinforcers), but the combined outcome of cocaine’s pharmacological effect with

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the animal’s volition to self-administer cocaine can produce a long-lasting potentiation of glutamate transmission onto VTA DA neurons.

4 Cocaine-Induced Synaptic Plasticity in the NAc The NAc is another integral part of the brain’s reinforcement circuit, and many studies indicate that synaptic plasticity in the NAc can be altered by cocaine exposure. Neuroplasticity of glutamatergic synapses onto medium spiny NAc neurons was first observed following passive, experimenter-administered cocaine injections (Thomas et al. 2001), which found LTD at these synapses. Interestingly, in contrast to the VTA where LTP is elicited after a single cocaine exposure, NAc synaptic plasticity was observed only after five daily cocaine injections (Kourrich et al. 2007; Thomas et al. 2001). However, after extended withdrawal from repeated cocaine exposure, mice show both cocaine-induced behavioral sensitization and LTP ex vivo in NAc shell but not core. This LTP is reversed back to the basal state if animals received a cocaine injection 24 h before recording. Thus, the history of cocaine exposure and withdrawal can readily change the direction of synaptic plasticity in the NAc. The behavioral consequence of NAc LTD after repeated amphetamine exposure was demonstrated in an elegant experiment whereby a GluR-trafficking modulator prevented both NAc LTD induction ex vivo and expression of behavioral sensitization to amphetamine (Brebner et al. 2005). In addition, unlike the VTA, AMPAR potentiation in the NAc following experimenter-administered amphetamine is not attributed to changes in the composition of AMPAR subunits, since analyses of rectification index revealed no rectification before or after amphetamine exposure. These results are consistent with the finding that blocking constitutive recycling of GluR2-containing AMPARs prevented NAc LTD and reduced expression of amphetamine-induced sensitization. In parallel to studies on plasticity in the VTA, plasticity in the NAc following chronic cocaine revealed differences whether cocaine was administered passively or by voluntary self-administration (Martin et al. 2006). In cocaine self-administering rats, the ability to induce LTD in the core and shell of the NAc was occluded one day after chronic cocaine. However, after 21 days of forced abstinence, LTD induction remained occluded in the NAc core, but could be readily induced in the NAc shell, suggesting that LTD in shell synapses had reverted to normal. These results suggest that voluntary cocaine self-administration induces long-lasting glutamatergic neuroadaptations exclusively in the NAc core, a region associated with control of behavior by drug-related stimuli and relapse to drug seeking. In support of this finding, a number of studies have observed increased NAc GluR1 levels after cocaine self-administration. Importantly, a recent study found an increase in cell surface GluR1 subunits in the NAc, during abstinence from cocaine self-administration (Conrad et al. 2008). Increased GluR1 levels are associated with an increase in rectification in synaptic AMPAR currents, as would be expected from plasma


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membrane insertion of GluR1-containing AMPARs. Importantly, to demonstrate that addition of GluR1-containing AMPARs plays a significant role in cue-induced cocaine relapse this study showed that intra-NAc injection of an antagonist selective for GluR1-containing AMPARs significantly reduced the enhancement in cocaine seeking that occurs after longer withdrawal times. In another recent study (Anderson et al. 2008), viral interference of GluR1 membrane insertion in the NAc shell attenuated drug-induced reinstatement. Although there are some differences in the methods used to elicit cocaine seeking in these studies (i.e., context re-exposure vs. drug-induced reinstatement), it is clear that accumbens GluR1 is important for the expression of cocaine-seeking behavior. In addition to altered AMPAR function, recent work has shown the importance of changes in the Homer proteins, scaffolding proteins that bind directly to mGluRs and indirectly to NMDARs, as critical neuroadaptations that can drive cocaine seeking (Swanson et al. 2001). Repeated cocaine and abstinence is associated with reduced NAc protein levels of Homer1b/c and Homer2a/b isoforms, and group I mGluRs (mGluR1 and mGluR5) (see also Mitrano et al. 2008). Activation of group I mGluRs within the NAc can increase NAc glutamate levels and produce locomotor activation. However, mGluR enhancement of NAc glutamate levels and locomotor activation is blunted after 3 weeks but not 24 h of withdrawal from repeated cocaine injection, in agreement with reduced mGluR and Homer protein levels.

5 Amygdala Plasticity and Drugs of Abuse Within the amygdala, there is a great degree of subregion heterogeneity. Two amygdala subregions have been of particular interest in the context of plasticity related to drug-seeking behavior. The basolateral amygdala (BLA; composed of the lateral, basomedial, basal and accessory basal nuclei) plays a critical role in associating environmental stimuli with primary rewards (Cador et al. 1989; Cardinal et al. 2002; Davis and Whalen 2001; LeDoux 2003, 2007; Maren and Quirk 2004), which may lead to relapse of drug seeking (Everitt et al. 1999; Robbins et al. 2008). The BLA is markedly different from the central nucleus of the amygdala (CeA) in both structure and function. The CeA is thought to play a critical role in the development of ethanol dependence, purportedly by modulating anxiety or stress that may increase ethanol intake (Bajo et al. 2008; Hyytia and Koob 1995; Koob, 2004, 2009; Rassnick et al. 1993b; Roberts et al. 1996). Drug conditioning plays a tremendous role in the persistence of drug addiction, and understanding how these learned responses are encoded is critical to developing drug addiction treatments. The lateral amygdala (LA), a dorsal subnucleus of the BLA, is a site of initial convergence for afferents transmitting sensory information about conditioned and unconditioned stimuli (Azuma et al. 1984; Doron and Ledoux 1999; LeDoux 2003; Maren and Quirk 2004; McDonald 1998; Nakashima et al. 2000). This may explain why the LA typically exhibits plasticity upon the acquisition of the association between a conditioned stimulus and a primary reward

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(Cador et al. 1989; Everitt et al. 1999; Jentsch et al. 2002; Thomas and Everitt 2001; Tronel and Sara 2002; Tye et al. 2008), while regions such as the VTA or NAc show robust molecular and synaptic changes after a single exposure to cocaine (Ghasemzadeh et al. 2003; Grignaschi et al. 2004; Ungless et al. 2001). It is likely that drugs act as powerful reinforcers by hijacking the natural reward circuitry, and that the amygdala-mediated formation of conditioned stimulus (CS) drug associations endows the CS with the power to maintain (Arroyo et al. 1998; Goldberg 1975; Goldberg et al. 1975), prolong (Ciccocioppo et al. 2004; Ranaldi and Roberts 1996) and induce reinstatement of drug-seeking behaviors (Fuchs et al. 2006; Grimm and See 2000; Kantak et al. 2002; Meil and See 1996; See et al. 2001). Relapse, which is often triggered by exposure to the drug, stress, or to cues associated with the drug experience, is a major clinical problem and one of the greatest challenges of addiction. In cocaine addicts, the presentation of cocaineassociated stimuli during abstinence can elicit intense drug craving (O’Brien et al. 1998), which is accompanied by physiological arousal, including increased heart rate and skin conductance (Childress et al. 1988; Ehrman et al. 1992), which corresponds to amygdala activation (Childress et al. 1999). The amygdala activation evoked by self-reported craving in humans is also observed in animals during drugseeking behaviors. Animal models can be utilized to explore the ability of environmental cues to guide reward-seeking behavior. Additionally, LTP has been observed in the lateral amygdala during cocaine withdrawal (Goussakov et al. 2006). While rats will readily lever press to self-administer primary reinforcers, such as sucrose, cocaine, or alcohol, they will also respond for reward-paired cues in the absence of the primary reward (Davis and Smith 1976; Grimm et al. 2002; Meil and See 1997; Nie and Janak 2003). The BLA has been shown to be necessary for second-order conditioning for both natural and drug rewards (Cador et al. 1989; Cardinal et al. 2002; Davis and Whalen 2001; LeDoux 2003, 2007; Maren and Quirk 2004). Moreover, evidence suggests that BLA function is specific to reinforcing properties of the reward-associated cue and does not affect reinforcing properties of the reward itself (Balleine et al. 2003). BLA lesions attenuate responding to a cue associated with a natural reinforcer such as sexual interaction, but do not alter sexual behavior itself (Everitt 1990). Furthermore, BLA lesions do not alter cocaine self-administration but attenuate the ability of cocaine-associated cues to reinstate extinguished responses (Meil and See 1997). Acute inactivation of the BLA prevents both cue-induced and drug priming-induced reinstatement to heroin-seeking behavior (Fuchs and See 2002). Other manipulations of the BLA, including muscarinic receptor antagonism (See et al. 2003), and DA receptor antagonism (Berglind et al. 2006) also impair the ability of cocaine-associated cues to induce reinstatement of cocaine-seeking behavior. It is also noteworthy that electrical stimulation of the BLA is sufficient to reinstate cocaine-seeking behavior (Hayes et al. 2003) and that LTP has been observed in the lateral amygdala during cocaine withdrawal (Goussakov et al. 2006). Importantly, extracellular concentrations of DA in the amygdala are tightly correlated with cocaine self-administration (Hurd and Ponten 2000). Specifically, intra-amygdala administration of selective DA antagonists reduces cocaine self-administration (Caine et al. 1995), and increasing or reducing


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the concentrations of DA in the amygdala can increase or reduce cocaine selfadministration (Hurd et al. 1997; Hurd and Ponten 2000). Whether these findings pertain to the cocaine-associated cues that are presented during self-administration or to the drug itself remains to be determined, but they clearly delineate a critical role for the amygdala in cocaine self-administration. The BLA is critically involved in the formation and expression of associations between sensory cues and rewarding or aversive stimuli (Davis and Whalen 2001; Gallagher 2000; LeDoux 2007; McGaugh 2002). Specifically, when animals are trained to respond to a reward that is paired with a predictive cue and responding is subsequently extinguished by the omission of the cue and reward, presentation of the cue alone increases responding. Evidence of BLA encoding of rewardassociated cues has been observed via in vivo electrophysiological recordings. BLA neurons are phasically excited during cocaine self-administration and by cocaine-associated cues (Carelli et al. 2003) as well as in response to cues associated with natural rewards such as sucrose (Tye and Janak 2007). Dynamic changes in local levels of immediate early genes indicate the occurrence of synaptic plasticity in the amygdala following activation or manipulation of stimulus-drug associations. For example, antagonism of the NMDAR has been shown to reduce the expression of the plasticity-related immediate early gene Zif268 during classical conditioning (Mokin and Keifer 2005). Furthermore, the protein products of immediate early gene Zif268 are upregulated in the BLA, but not the CeA, following exposure to discrete cues previously associated with cocaine self-administration (Thomas et al. 2003). The infusion of Zif268 antisense oligodeoxynucleotides into the BLA abolished the previously acquired conditioned reinforcing properties of the drug-associated stimulus (Lee et al. 2005). Acute NMDAR antagonism in the BLA prior to memory reactivation also disrupted the drug-associated memory, impairing the ability of the cocaine-associated cue to exert its acquired conditioned reinforcing properties, and resulted in reduced expression of Zif268 (Milton et al. 2008). In contrast to the BLA, the CeA is widely considered to be critically involved in mediating the behavioral effects of ethanol (Gilpin et al. 2008; Koob, 1998, 2003, 2004, 2009; Koob et al. 1998; McBride et al. 2005; Richter et al. 2000; Roberto et al. 2004a, b). There is a strong connection between anxiety states and alcohol dependence (Heilig and Egli 2006; Koob 2003, Pandey et al. 2003). Acute ethanol exposure induces anxiolytic effects associated with increased brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (trk B) expression, increased expression of the immediate early gene activity-regulated cytoskeleton-associated protein (Arc), and increased dendritic spine density in the CeA, but not the BLA (Pandey et al. 2008). The activation of neuropeptide Y (NPY) in the CeA can impair the motivational aspects associated with ethanol dependence (Pandey et al. 2003). Specifically, administration of NPY into the CeA attenuates the increase in drug intake associated with alcohol dependence (Gilpin et al. 2008; Thorsell et al. 2007). In vivo microdialysis and in vitro electrophysiological studies revealed that both acute and chronic ethanol alter glutamatergic transmission in the CeA (Roberto et al. 2004b). Taken together, this constellation of ethanol-related neuroadaptations

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strongly implicates the critical involvement of the CeA in alcohol abuse and dependence. The CeA is heavily involved in the anxiety related to ethanol withdrawal (Koob 2003; McBride et al. 2002), as multiple measurable changes occur in the CeA during withdrawal. Accumulating evidence shows that acute withdrawal from many drugs of abuse, including cocaine (Fu et al. 2007; Richter and Weiss 1999) and alcohol (Funk et al. 2006; Koob 2003; Merlo Pich et al. 1995; Olive et al. 2002) produce common increases in reward thresholds, anxiety-like responses, and extracellular levels of CRF in the CeA. Understanding the anxiety related to ethanol withdrawal involves a complex neurobiology involving the interaction of multiple systems. The CRF and norepinephrine systems have been shown to be closely entwined in the amygdala (Dunn et al. 2004; Emoto et al. 1993; Roozendaal et al. 2008; Smith and Aston-Jones 2008), as they reciprocally activate one another (Koob 1999a, b). Both ethanol and CRF enhance GABA release in the CeA (Nie et al. 2004) via a common pathway involving protein kinase C epsilon (Bajo et al. 2008). Another substrate for withdrawal-related anxiety is in cAMP-responsive element-binding (CREB) phosphorylation in the CeA, which is decreased during withdrawal following chronic ethanol exposure (Pandey et al. 2003). Additionally, partial deletions and deficits in amygdaloid (CREB) protein contribute to increased ethanol consumption and a predisposition to alcoholism and alcohol-related anxiety (Pandey 2004; Pandey et al. 2005).

6 Alcohol and Plasticity in Glutamate Receptors Alcohol abuse is considered the third leading preventable cause of human death (Mokdad et al. 2004). Also, because it is legal to obtain and linked to increased aggression and violence, alcoholism extracts enormous social and economic costs relative to other drugs of abuse (see Buck and Harris 1991; Harwood et al. 1998; Larimer et al. 1999; Sanchis-Segura and Spanagel 2006). Thus, changes in neuronal function after long-term alcohol intake that contribute to pathological, compulsive alcohol seeking and relapse are of great interest. In particular, alcohol seeking and intake occurs even in the face of detrimental consequences, which represents a major clinical hurdle during the process of overcoming alcohol use disorders. Interestingly, in humans, relapse to alcohol seeking is commonly associated with the appearance of negative affective states or other stressful events, as well as to alcohol-related cues (Larimer et al. 1999; Sanchis-Segura and Spanagel 2006). Relapse can thus be associated with more stressful and psychological symptoms early during withdrawal, or can be associated with increased susceptibility for relapse even after prolonged abstinence. Further, rodent studies have suggested that stress- and cue-related enhancement of drug seeking are critically regulated by the VTA and by target regions of the VTA such as the NAc (see Kalivas and McFarland 2003; Wang et al. 2007), where DA release can interact with


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glutamate-driven firing to modulate expression of behavior. Thus, we will first focus on changes in glutamatergic function in the VTA and NAc after alcohol. A number of studies using diverse alcohol exposure models have examined the effect of repeated alcohol exposure on NMDA receptor function, and several brain regions, including the NAc/striatum, show enhanced NMDAR function during early withdrawal from alcohol (Buck and Harris 1991; Dodd et al. 2000; Gulya et al. 1991; Siggins et al. 2003; Szumlinski et al. 2008a, b; Wang et al. 2007; Zhao and Constantine-Paton 2007); but see (Winkler et al. 1999). In general, increased NMDAR function during withdrawal from alcohol is thought to increase neuronal excitability and drive aversive withdrawal symptoms that increase alcohol consumption. Given the role of negative emotional and physical states in promoting alcohol seeking, NMDAR inhibitors are an attractive clinical intervention to reduce early withdrawal symptoms and decrease relapse during early withdrawal. The exact change in particular NMDAR subunit levels varies among brain regions and alcohol exposure. In the NAc, both NR1 and NR2B have been found to be increased during early withdrawal from alcohol, in addition to increased mGluR1 and Homer 2b (see below) (Szumlinski et al. 2008a, b; Zhao and Constantine-Paton 2007). Some studies have also observed alterations in NMDAR function without changes in subunit levels. For example, long-term alcohol intake can strongly upregulate the NR1-2 isoform in the NAc, which lacks an NR1 C1 cassette that is necessary for efficient trafficking or anchoring of NMDARs to the postsynaptic density, and the pattern of functional changes in NMDAR depends on whether alcohol exposure is intermittent or continuous (Zhao and Constantine-Paton 2007). In the VTA, chronic forced alcohol is associated with increased NMDAR subunit levels (Ortiz et al. 1995), although one study found reduced NMDA excitation of VTA firing in vitro during withdrawal from alcohol (Bailey et al. 1998). In addition to NMDAR changes, VTA AMPAR function is enhanced after alcohol self-administration (Stuber et al. 2008a), in agreement with an earlier study showing increased VTA GluR1 levels after long-term forced alcohol intake (Ortiz et al. 1995). Although enhanced glutamate receptor function might increase VTA excitability (Canavier and Landry 2006), early withdrawal from alcohol is associated with a decrease in activity of VTA neurons and a decrease in DA release in VTA terminal regions (Bailey et al. 1998; Diana et al. 1993; Weiss et al. 1996). This hypoactivity of the DA system is reversed by systemic inhibition of NMDARs (Rossetti et al. 1992). Thus, NMDARs in a brain region other than the VTA may control VTA firing activity during early withdrawal from alcohol. Importantly, self-administration of alcohol during withdrawal continues until NAc DA levels are normalized (Weiss et al. 1996), in agreement with observations that modulation of alcohol intake is sensitive to altering DA signaling in the NAc (Hodge et al. 1997; Rassnick et al. 1993a; Rassnick et al. 1993b; Samson and Chappell 2004) or altering VTA DA neuron activity (Hodge et al. 1993; Rodd et al. 2004). Finally, although VTA DA neurons may exhibit hypoactivity during withdrawal from alcohol, enhanced NMDAR and AMPAR function in the VTA after chronic alcohol could facilitate VTA neuron activity during consumption of alcohol, since alcohol exposure can facilitate VTA neuron firing

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(Brodie et al. 1990; Diana et al. 1993; Mereu et al. 1984) and increases DA release in the NAc (Gonzales and Weiss 1998). Of potentially great interest are possible long-term changes in VTA glutamatergic function after longer withdrawal from alcohol that may parallel alterations in glutamatergic function in both the NAc and VTA after withdrawal from cocaine self-administration (see above). In particular, enhanced glutamatergic throughput could increase firing of NAc or VTA neurons and modulate alcohol intake or facilitate relapse in the presence of alcohol-related conditioned stimuli. Altered glutamatergic function after long-term withdrawal from alcohol has been found in the NAc, where a different pattern of changes is observed relative to cocaine exposure. After alcohol, the NAc shows increases rather than decreases in NR2B, mGluR1, and Homer2b (see Szumlinski et al. 2008a, b). These altered glutamate receptor levels are observed after 2 weeks withdrawal following 3 months of alcohol drinking; after 2 months withdrawal, only an increase in Homer2b is observed. Changes in all three glutamate receptor proteins also are observed after short-term passive exposure or binge drinking (Szumlinski et al. 2008a, b; Zhao and Constantine-Paton 2007), and thus the time course of glutamate receptor changes may vary depending upon the duration and route of alcohol exposure. Interestingly, viral overexpression of Homer2b in the NAc increases alcohol preference and alcohol-related place preference, suggesting that mimicking the drinking-induced enhancement in Homer2b is sufficient to increase alcohol preference and reinforcement. Interestingly, overexpression of Homer2b in the NAc increases alcoholrelated NAc glutamate and DA release. This pattern has been associated with increased alcohol preference, and is also linked to regulation of glutamate release by mGluR1/5. Thus, increased NAc Homer2b levels, acting through trafficking of mGluRs and modulation of glutamate release, could facilitate the reinforcing effects of alcohol after chronic intake, and in this way promote alcohol seeking during withdrawal.

7 Altered Intrinsic Excitability After Alcohol or Cocaine In addition to modulation of neuronal excitability through plastic changes in glutamate receptor function, a number of studies in recent years have investigated the possibility that plastic changes in ion channel function can occur and be longlasting. Further, such intrinsic excitability changes could alter the ability of synaptically generated excitatory postsynaptic currents (EPSCs) to propagate along dendrites in order to influence action potential generation and neuronal firing. Thus, numerous ion channels in dendrites can amplify or retard passing EPSCs and greatly impact the ability of glutamate receptor activation to generate action potentials and generate LTD or LTP (Kauer and Malenka 2007). Particularly interesting is the possibility that persistent alterations in ion channel function could dramatically enhance the ability of relapse-inducing stimuli to drive firing of the VTA and NAc, and in this way promote craving and relapse.


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L-type voltage-gated calcium channels (LVGCC) are notably interesting, since altered LVGCC function seems to occur during early withdrawal from many abused drugs including alcohol, and thus could represent a common mechanism (for review, see Brooks et al. 2008; Buck and Harris 1991; Little 1999). Chronic alcohol exposure increases LVGCC levels in brain regions such as the hippocampus, with more mixed results in the few studies from the striatum (Lucchi et al. 1985; Woodward and Gonzales 1990). Also, systemic administration of LVGCC antagonists decreases alcohol withdrawal symptoms and the decreased DA levels normally evident during early withdrawal from alcohol and other drugs. Human studies are less clear with regard to changes in LVGCC in the brains of alcoholics (Kril and Harper 1989; Marks et al. 1989). However, there are human preclinical studies indicating that LVGCC antagonists may ameliorate early withdrawal symptoms, as well as reducing tolerance and cravings, with clearer evidence for drugs other than alcohol (Altamura et al. 1990; Rosse et al. 1994; Rush and Pazzaglia 1998). Interestingly, LVGCC in the striatum are required for induction of LTD (see Adermark and Lovinger 2007), and NAc LTD is necessary for the expression of behavioral sensitization to amphetamine (Brebner et al. 2005). While the mechanism underlying this requirement for LTD in behavioral sensitization is unknown, increased LVGCC levels could promote LTD induction after drug exposure and facilitate the development or expression of behavioral sensitization. Thus, like the NMDARs, LVGCC inhibitors may be a useful clinical intervention to counteract early withdrawal symptoms, even though the brain regions where LVGCC plasticity occurs and is necessary for withdrawal symptoms have not been clearly identified (see Whittington and Little 1991). Considerable work has examined changes in NAc ion channel activity after repeated cocaine injection and 3 days withdrawal. A number of functional changes that decrease intrinsic excitability are apparent in the NAc during withdrawal from cocaine, including increased potassium channel activity, decreased N- and R-type VGCC activity, and decreased sodium channel activity (Hu et al. 2004, 2005; Zhang et al. 2002). Also, calcium channels can regulate a number of physiological processes in addition to firing, including induction of glutamatergic plasticity, neurotransmitter release, and calcium-dependent activation of intracellular regulatory proteins such as kinases. These changes may reflect increased or decreased ion channel protein levels, but some cocaine-associated changes in channel function may be related to altered tonic activity of intracellular signaling molecules and ion channel phosphorylation or other modifications. Thus, as for NMDARs, investigations of plastic changes in receptor or channel function after chronic drug exposure need to carefully consider the many different regulatory steps that can impact activity of a receptor or channel, such as phosphorylation, trafficking, and membrane localization, since these might provide important information about potential therapeutic targets to reverse drug-related neuroadaptations that could facilitate relapse. Such psychostimulant-related changes in intrinsic excitability are not limited to the NAc, and have also been identified in the prefrontal cortex and subiculum (Cooper et al. 2003; Nasif et al. 2005).

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VTA DA neuron firing after alcohol exposure has also been studied. A number of groups have observed a reduction in firing during the first 1–6 days of withdrawal from alcohol (Bailey et al. 1998; Brodie 2002; Diana et al. 1993), a pattern also observed after withdrawal from exposure to other drugs of abuse (Ackerman and White 1992; Rossetti et al. 1992). However, the possible contribution of particular ion channels in this decreased VTA neuron excitability is poorly understood. Nonetheless, given the possible involvement of DA receptors in the regulation of many forms of alcohol- and drug-related behaviors (see above), changes in VTA ion channel function that persist beyond the early withdrawal period are of great interest. A recent study found that the function of the apamin-sensitive, SK-type calcium-activated potassium channel was significantly reduced in VTA DA neurons after 7 days withdrawal following repeated alcohol exposure (Hopf et al. 2007). Although alcohol exposure did not alter baseline firing rates, NMDA receptor activation increased burst firing in alcohol-treated animals, but increased the spike firing rate of VTA neurons in control animals. These findings are consistent with reductions in SK-type potassium channels in alcohol-treated animals, since inhibition of these channels facilitates glutamate-induced bursting in midbrain DA neurons (Johnson and Seutin 1997; Seutin et al. 1993; Waroux et al. 2005). Since bursting is associated with increased DA release in VTA terminal regions (see Grace 2000; Marinelli et al. 2006), reduced SK function could enhance DA release in response to alcohol-related stimuli and promote relapse to alcohol seeking. A small reduction in the Ih current was also observed after 7 days withdrawal from alcohol (Hopf et al. 2007), which was also observed after one day of withdrawal (Okamoto et al. 2006). Reduced Ih function did not change burst firing, but decreased the ability of VTA DA neurons to recover from hyperpolarization. Of particular importance are neuroadaptations that are evident after even longer periods of abstinence from alcohol. Alcoholism is considered a chronically relapsing disease (Larimer et al. 1999; Sanchis-Segura and Spanagel 2006), and neuroadaptations that persist for months to years of abstinence could play a critical role in the increased propensity for relapse in human alcoholics. In this regard, a recent study from our group observed reduced SK channel function in the NAc core after 3 weeks abstinence from alcohol self-administration, but not after abstinence from sucrose self-administration. Importantly, infusion of an SK activator into the NAc core reduced alcohol seeking but not sucrose seeking. In addition, the lateral dorsal striatum exhibited a strong basal SK regulation of firing (Pineda et al. 1992), which was not reduced during abstinence from alcohol selfadministration, and SK activators infused into the lateral dorsal striatum did not reduce alcohol seeking. Thus, SK activators were only effective in modulating alcohol seeking in regions where SK function was reduced, suggesting that SK activators might represent a novel therapeutic intervention in abstinent alcoholics. We hypothesize that decreased SK function in NAc core will enhance firing in NAc core neurons during exposure to alcohol-related stimuli, and so reduced NAc core SK function could promote behavioral activation by these alcohol-related stimuli and drive relapse. In addition, SK inhibition in the NAc is in agreement


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with an early study showing that abstinence after long-term alcohol exposure was associated with a reduced after hyperpolarization in the dentate gyrus (Durand and Carlen 1984) that is strongly although not uniquely mediated by SK potassium channels (Gu et al. 2005). Thus, results from multiple complementary techniques, including in vitro electrophysiology, biochemistry, and gene chip and proteomic studies have identified changes in SK and other ion channels and receptors after alcohol exposure. Additional behavioral pharmacology experiments have suggested that at least some of these neuroadaptations could represent critical changes in the NAc and other brain regions that might promote alcohol seeking during abstinence from alcohol.

8 Conclusions and Future Directions Although many important and tantalizing clues regarding the effect of chronic drug and alcohol exposure on plasticity in glutamate receptor and ion channel function have been demonstrated, many questions remain. Few studies have examined excitability changes beyond the period of early withdrawal, although recent studies of glutamate receptor and ion channel function have begun to characterize changes after long-term withdrawal from cocaine, alcohol, or heroin exposure. Identifying long-term changes is particularly critical since neuroadaptations persisting after weeks or months of abstinence may mediate long-term susceptibility to cravings and relapse. Importantly, these long-term neuroadaptations may also correlate with structural changes in spine density or dendritic architecture that can occur in the NAc after passive or active cocaine administration. It is also clear that selfadministration and passive administration of abused drugs can differentially alter gene expression and protein function (see Jacobs et al. 2002, 2004), perhaps due to learned cues that come to be associated with the act of voluntary self-administration and that can reinforce further alcohol or drug seeking in a conditioned, involuntary manner. Fortunately, the field possesses a battery of powerful techniques including membrane isolation and traditional Western Blot protein analyses, large scale genomic and proteomic methods, optogenetics, and ex vivo brain slice electrophysiology from animals that have learned to self-administer cocaine or alcohol. Although laborious and technically challenging in adult animals, we believe that ex vivo electrophysiology is especially critical for uncovering and defining which neuroadaptations might persist during abstinence, in part because potent functional changes can occur without altered total protein or mRNA levels. The advent of localized knockdown or cell-specific over expression of proteins of interest will aid in determining their functional role in addictive behavior. In addition, a more clear delineation of the molecular alterations apparent after abstinence could allow one to utilize specific pharmacological or molecular agents to reverse that harmful effects of molecular change (e.g., reversing the plasma membrane trafficking of particular AMPAR subunits), and perhaps provide a novel therapeutic intervention for addiction and alcoholism.

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Dopamine Signaling in the Nucleus Accumbens of Animals Self-Administering Drugs of Abuse Ingo Willuhn, Matthew J. Wanat, Jeremy J. Clark, and Paul E. M. Phillips

Contents 1

2

3

4

The Dopamine System: Implication in Normal Behavior and Addiction . . . . . . . . . . . . . . . . . . 31 1.1 Drug Addiction and Dopamine Neurotransmission in Humans . . . . . . . . . . . . . . . . . . . . . . . 31 1.2 Drug Self-Administration as an Animal Model for Drug Addiction . . . . . . . . . . . . . . . . . . 31 1.3 Drug-Self-Administration and Dopamine in the Nucleus Accumbens . . . . . . . . . . . . . . . . 32 1.4 Anatomy of the Dopamine System and Dopamine Signal Transduction: Phasic and Tonic Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 1.5 Proposed Functions of Dopamine in the NAcc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Dopamine Detection in the Behaving Animal: In Vivo Microdialysis, Chronoamperometry, and Fast-Scan Cyclic Voltammetry (FSCV) . . . . . . . . . . . . . . . . . . . . . . . . 36 2.1 In Vivo Microdialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 2.2 Electrochemical Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Effects of Drugs of Abuse on Extracellular Dopamine Concentration in the NAcc . . . . . . . 38 3.1 The Dopamine Hypothesis of Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 3.2 Drug Effects on Dopamine Signaling Measured Over the Course of Minutes: Microdialysis Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 3.3 Drug Effects on Dopamine Signaling Measured Over the Course of Seconds to Hours: Chronoamperometry Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 3.4 Drug Effects on Dopamine Signaling Measured on a Subsecond Time Scale: FSCV Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 3.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Effects of Withdrawal from Drugs of Abuse on the NAcc Dopamine System . . . . . . . . . . . . 46 4.1 Tonic Dopamine During Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 4.2 Phasic Dopamine During (Short-Term) Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

I. Willuhn (*), M.J. Wanat, J.J. Clark, and P.E.M. Phillips Department of Psychiatry and Behavioral Sciences and Department of Pharmacology, University of Washington, Health Sciences Building, Box 356560, 1959 NE Pacific Street, Seattle, WA, 98195, USA e-mail: [email protected]


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Stimulus-Induced NAcc Dopamine Release in the Absence of Drug: Implications for Reinstatement of Drug Seeking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 5.1 Effects of Drug Cues on Tonic Dopamine Concentration in the NAcc . . . . . . . . . . . . . . . 49 5.2 Effects of Drug Cues on Phasic Dopamine Signaling in the NAcc . . . . . . . . . . . . . . . . . . . 50 6 The Role of NAcc Dopamine in Drug Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 6.1 Motivation and Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 6.2 Associative Learning and Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 7 Different Functions for Phasic and Tonic Dopamine Transmission in Addiction . . . . . . . . . . 53 7.1 Dopamine Signaling in the Drug-Naı¨ve State (Fig. 2a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 7.2 Immediate Effects of Drug Exposure (Fig. 2b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 7.3 Long-Term Effects of Drug Exposure During Drug Withdrawal (Fig. 2c) . . . . . . . . . . . 57 8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Abstract Abuse of psychoactive substances can lead to drug addiction. In animals, addiction is best modeled by drug self-administration paradigms. It has been proposed that the crucial common denominator for the development of drug addiction is the ability of drugs of abuse to increase extracellular concentrations of dopamine in the nucleus accumbens (NAcc). Studies using in vivo microdialysis and chronoamperometry in the behaving animal have demonstrated that drugs of abuse increase tonic dopamine concentrations in the NAcc. However, it is known that dopamine neurons respond to reward-related stimuli on a subsecond timescale. Thus, it is necessary to collect neurochemical information with this level of temporal resolution, as achieved with in vivo fast-scan cyclic voltammetry (FSCV), to fully understand the role of phasic dopamine release in normal behavior and drug addiction. We review studies that investigated the effects of drugs of abuse on NAcc dopamine levels in freely moving animals using in vivo microdialysis, chronoamperometry, and FSCV. After a brief introduction of dopamine signal transduction and anatomy and a section on current theories on the role of dopamine in natural goal-directed behavior, a discussion of techniques for the in vivo assessment of extracellular dopamine in behaving animals is presented. Then, we review studies using these techniques to investigate changes in phasic and tonic dopamine signaling in the NAcc during (1) response-dependent and -independent administration of abused drugs, (2) the presentation of drug-conditioned stimuli and operant behavior in self-administration paradigms, (3) drug withdrawal, and (4) cue-induced reinstatement of drug seeking. These results are then integrated with current ideas on the role of dopamine in addiction with an emphasis on a model illustrating phasic and tonic NAcc dopamine signaling during different stages of drug addiction. This model predicts that phasic dopamine release in response to drug-related stimuli will be enhanced over stimuli associated with natural reinforcers, which may result in aberrant goal-directed behaviors contributing to drug addiction. Keywords Dopamine Drug self-administration Drugs of abuse Nucleus accumbens Drug addiction Fast-scan cyclic voltammetry Phasic and tonic dopamine signaling

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1 The Dopamine System: Implication in Normal Behavior and Addiction 1.1

Drug Addiction and Dopamine Neurotransmission in Humans

Abuse of psychoactive substances can lead to drug addiction, a maladaptive behavioral pattern of drug use that is often accompanied by drug tolerance and withdrawal symptoms and causes impairment, distress, and the habitual intake of the drug regardless of the devastating consequences (Diagnostic and Statistical Manual of Mental Disorders (DSM-IV); APA 2000). An estimated 5% of the world’s population aged 15–64 years used illicit psychoactive drugs in the past year (UN 2008). Legal psychoactive drugs, such as alcohol and tobacco, are used by at least one-quarter of the world’s adult population (UN 2008). Drug addiction is considered to be a chronic disorder because addicts are rarely able to maintain abstinence for extended periods of time despite an expressed desire to stay drugfree. This is because stress, re-exposure to the drug itself, and drug-associated cues often trigger the resumption of drug taking (Kalivas and McFarland 2003). Such cues can even promote drug-seeking behavior outside of awareness that eventually results in relapse to drug taking (Tiffany and Carter 1998). Evidence shows that drugs of abuse affect dopamine neurotransmission. Imaging studies revealed that drug-naı¨ve individuals show enhanced dopamine levels in the striatum upon exposure to psychostimulants such as cocaine and amphetamine (Volkow et al. 1997a; Drevets et al. 2001). In contrast, decreased striatal dopamine responses were reported in detoxified cocaine abusers (Volkow et al. 1997b). Furthermore, individuals with a history of abuse of alcohol (Volkow et al. 1996), cocaine (Volkow et al. 1990), heroin (Wang et al. 1997), or methamphetamine (Volkow et al. 2001) display lower levels of dopamine receptor binding compared to nonabusers (Volkow et al. 2004). Together, these imaging studies suggest an involvement of dopamine neurotransmission in the acute and long-term effects of abused drugs.

1.2

Drug Self-Administration as an Animal Model for Drug Addiction

To better understand the neurobiology of drug abuse and addiction in humans, several animal models have been developed to investigate different aspects of drug addiction (Koob and Le Moal 2008). Among these models, paradigms that incorporate self-administration of drugs are thought to best capture the human condition because animals are allowed to voluntarily seek the drug and because drugs that are self-administered by animals correspond well with those that have high abuse

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potential in humans (Koob and Le Moal 2008). However, a great number of studies have examined the effects of drugs of abuse upon passive injection by the experimenter (noncontingent or response-independent administration). Therefore, in this chapter, we will review studies that have used contingent or responsedependent (self-administration), as well as noncontingent or response-independent drug injections.

1.3

Drug-Self-Administration and Dopamine in the Nucleus Accumbens

Dopamine neurotransmission is highly implicated in the regulation of reinforcement in rodent drug self-administration paradigms. The dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) has been identified as a critical substrate for the expression of drug reinforcement (Ritz et al. 1987; Wise and Bozarth 1987; Koob and Bloom 1988; Kalivas and McFarland, 2003). For example, direct dopamine receptor agonists are selfadministered systemically as well as locally into the NAcc (Yokel and Wise 1978; Woolverton et al. 1984; Carlezon et al. 1995). Dopamine receptor antagonists administered systemically in low doses increase the rate of operant responding for cocaine in animals (De Wit and Wise 1977; Ettenberg et al. 1982; Roberts and Vickers 1984; Britton et al. 1991; Corrigall and Coen 1991; Caine and Koob 1994; Hemby et al. 1996), but decrease the motivation to carry out high work requirements to obtain an infusion of cocaine (Hubner and Moreton 1991; Richardson et al. 1993). Similarly, intracerebral administration of dopamine antagonists into the NAcc increases the rate of psychostimulant self-administration (Maldonado et al. 1993; Phillips et al. 1994), but decreases responding when work requirements for the drug infusion increase (McGregor and Roberts 1993). These effects have been interpreted as an attenuation of the reinforcing properties of the drug, such that more drug is taken to achieve the same level of reward, and that less effort is invested into a drug infusion with decreased rewarding properties. In contrast, lesion or inactivation of the mesolimbic dopamine system in the VTA (Roberts and Koob 1982; Shoaib et al. 1998; Xi and Stein 1999) or the NAcc (Roberts et al. 1977, 1980; Lyness et al. 1979; Pettit et al. 1984; Corrigall et al. 1992; Shoaib et al. 1998) attenuate cocaine, amphetamine, heroin, and nicotine self-administration in rats. These findings further underline the critical importance of the mesolimbic dopamine system in drug taking. However, there are some conflicting reports on whether dopamine antagonists or lesions of the mesolimbic dopamine system affect responding for all drugs of abuse (Pettit et al. 1984; Hemby et al. 1996; Di Chiara 2000; Czachowski et al. 2001). Notably, the response of the NAcc dopamine system to drug administration (discussed later) differs significantly depending on whether the animal actively self-administers a drug of abuse or whether the animal receives it independent of a response (Hemby et al. 1995, 1997; Lecca et al. 2007).


1.4

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Anatomy of the Dopamine System and Dopamine Signal Transduction: Phasic and Tonic Release

The VTA and the neighboring substantia nigra are the primary dopamine-producing nuclei in the brain (Swanson 1982). From these midbrain nuclei, relatively distinct dopamine cell groups innervate different functional domains of the striatum; i.e., sensorimotor, associative, and limbic circuits that are mainly defined by their differential cortical inputs (Carlsson et al. 1962; Dahlstrom and Fuxe 1964; Alexander and Crutcher 1990; Joel and Weiner 2000). The VTA predominantly projects to the limbic striatum including the NAcc. More than three-quarters of this mesolimbic projection stems from dopaminergic neurons (Swanson 1982). Dopamine acts on D1- or D2-type dopamine receptors upon release from dopaminergic fibers that densely innervate the striatum (Doucet et al. 1986; Ritz et al. 1987; Groves et al. 1994). Dopamine receptors are found at symmetric boutons formed by dopaminergic terminals on the neck or shaft of the spines of striatal projection neurons (Levey et al. 1993; Groves et al. 1994; Hersch et al. 1995; Caille et al. 1996). However, dopamine receptors are often found on striatal dendrites outside such synapses, in the vicinity of asymmetric boutons on the head of dendritic spines that are contacted by glutamatergic terminals (Levey et al. 1993; Caille et al. 1996). Stimulation of dopamine receptors is terminated by reuptake of extracellular dopamine into the presynaptic terminals. Most dopamine reuptake sites are located on dopaminergic fibers outside synaptic contacts of dopaminergic terminals (Nirenberg et al. 1996; Hersch et al. 1997), similar to the dopamine receptors. Together, this distribution of receptors and reuptake sites allows for “volume transmission”; i.e., the activation of extrasynaptic dopamine receptors by dopamine that diffuses a few micrometers away from its release into the synaptic cleft (Garris et al. 1994; Garris and Rebec 2002; Rice and Cragg 2008). Therefore, the measurement of extracellular dopamine concentrations is a meaningful indicator of dopamine signaling. Dopamine neurons are either hyperpolarized/quiescent or display different patterns of discharge activity: single-spike firing (2–10 Hz) or bursts of 2–6 action potentials (15–30 Hz) (Grace and Bunney 1984a, b; Freeman and Bunney 1987). Individual dopamine neurons can switch from one of these patterns to the other, as shown in freely moving rats (Freeman and Bunney 1987; Hyland et al. 2002). Salient sensory stimuli can evoke a transient increase in firing rate and burst firing (Freeman and Bunney 1987; Mirenowicz and Schultz 1996). The “tonic” extracellular concentration of dopamine, ranging from 5 to 20 nM depending on the target area, is thought to arise from basal dopamine neuron firing patterns, which predominantly consists of single-spike firing (Bunney et al. 1991; Grace 1991; Parsons and Justice 1992; Keefe et al. 1993; Floresco et al. 2003). Conversely, burst firing of dopamine neuron populations is thought to give rise to “phasic” dopamine events which can reach as high as 1 mM (Gonon 1988; Chergui et al. 1994; Garris et al. 1997). In support of this assertion, it has been shown that electrical stimulations mimicking burst firing are much more potent in triggering dopamine overflow than

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single pulse stimulations (Wightman and Zimmerman 1990; Chergui et al. 1996; Gonon and Sundstrom 1996). In summary, the signaling modes that govern communication between dopamine neurons and their target cells are rapid and transient increases in dopamine concentrations (phasic dopamine) on top of a low, slowly changing dopaminergic tone (tonic dopamine).

1.5

Proposed Functions of Dopamine in the NAcc

Since the identification of dopamine over 50 years ago (Carlsson et al. 1957), a number of ideas have been developed to explain the role of dopamine in behavior. These ideas (some of which are presented below) are not necessarily mutually exclusive, but rather focus on different aspects of dopamine function in behavior. The most uncontroversial of ideas is that dopamine is implicated in motor function (Berridge 2007; Salamone and Correa 2002) as selective degeneration of dopamine neurons in Parkinson’s disease patients or animals treated with neurotoxins causes motor deficits (Sundstrom et al. 1990; Schwarting and Huston 1996; Galvan and Wichmann 2008). However, these motor deficits are considered to be caused primarily by compromised dopamine signaling in the dorsal striatum, whereas dopamine in the ventral striatum including the NAcc is assumed to be part of a “limbic motor interface” (Mogenson et al. 1980). This idea is based on the fact that NAcc neurons receive input from limbic brain regions and send output to motor brain regions. For example, dopamine infused into the NAcc caused an increase in locomotion that can be inhibited by blocking the effect of NAcc output in one of its motor output nuclei (Jones and Mogenson 1980), supporting the proposition that NAcc dopamine serves as a modulator in the translation of motivation into action (Mogenson et al. 1980). 1.5.1

Dopamine and Motivated Behavior

Mogenson’s pioneering work inspired research that produced many lines of evidence supporting a critical role of dopamine in motivation and effort (Salamone and Correa 2002; Berridge 2007). For example, the impact of manipulations that impair dopamine signaling in the NAcc on food-seeking behavior is critically dependent upon the work requirements of the task (e.g., Salamone et al. 1991; Cousins and Salamone 1994). Thus, food-seeking that requires low effort is largely unaffected by partial NAcc dopamine depletions, whereas food-seeking that requires high effort is substantially impaired (e.g., Salamone et al. 1994; Denk et al. 2005). This suggests that dopamine may be implicated in overcoming the motivational costs required for completing tasks that involve a high level of effort (Salamone and Correa 2002; Phillips et al. 2007). Similarly, we recently suggested that NAcc dopamine, influenced by internal deprivation states (e.g., hunger and thirst), plays a key role in overcoming response costs by modulating activity originating from the frontal cortical systems that assess costs and rewards (Phillips et al. 2007). This may


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enable mesolimbic dopamine to energize goal seeking and affect cost-benefit decision making. The “incentive-salience” hypothesis of dopamine also builds upon the involvement of dopamine in motivation (Robinson and Berridge 1993; Berridge 2007). In short, incentive salience is the neural representation of motivational value in response to a reward-related stimulus that drives behavior. Dopamine in the NAcc is thought to modulate the incentive value of such reward-related stimuli (Berridge 2007). The hypothesis distinguishes between “liking” of rewards (hedonic value) and “wanting” of rewards (incentive value) (Berridge 2007). For example, enhancing dopamine levels in dopamine transporter knock-down mice increases the “wanting” of food reinforcers (Pecina et al. 2003; Cagniard et al. 2006a), whereas “liking” of food reinforcers is not affected by insults to the function of the dopamine system (Berridge et al. 1989; Pecina et al. 1997). This supports the proposition that NAcc dopamine is implicated in “wanting” or the “incentive value” of a stimulus.

1.5.2

Dopamine and Reinforcement Learning

The most compelling line of evidence for a role of dopamine in reinforcement learning comes from the firing patterns of dopamine neurons during the presentation of conditioned and unconditioned stimuli (Schultz et al. 1997). Initially, these neurons show synchronous firing patterns in response to the delivery of unpredicted rewards. After repeated pairing with a stimulus that predicts reward, dopamine neurons cease firing to reward delivery and instead respond to the cue that predicts its availability (Schultz et al. 1997; Waelti et al. 2001). This firing pattern of dopamine cells is consistent with a reward prediction signal that provides the organism with the capacity to compare the expected outcome to the actual outcome, in order to maximize reward (Montague et al. 2004). An unexpected reward following a neutral cue is a positive error and favors learning. The omission of an expected reward after a predictive cue or action is a negative error and favors extinction. In support, it has been shown that dopamine neuron firing correlates with the magnitude of the reward (Tobler et al. 2005). However, some have argued it is unlikely that dopamine serves as a teaching signal given the limited availability of afferent sensory processing and the precise timing of dopamine signals (Redgrave and Gurney 2006). Instead, it has been suggested that dopamine may contribute to a more simple, low-computation process, leading to the identification of which aspects of context and behavioral output are crucial in causing unpredicted events (Redgrave and Gurney 2006). All of the above presented evidence and theoretical framework implicate NAcc dopamine in motivation and/or reinforcement learning. What becomes evident after examining these different lines of research is that the mesolimbic dopamine system is associated with a diverse array of behaviors, which illustrate that dopamine may mediate various functions depending upon the temporal dynamics, location, and context of its release (Schultz 2007). Specifically, the functional impact of phasic and tonic dopamine release may differ, as we will explore below.

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2 Dopamine Detection in the Behaving Animal: In Vivo Microdialysis, Chronoamperometry, and Fast-Scan Cyclic Voltammetry (FSCV) A number of analytical techniques are utilized to chemically detect extracellular dopamine in vivo. These techniques differ in their time resolution ranging from milliseconds to hours. Thus, some are best suited to detect tonic changes, while others are optimized for isolating phasic dopamine release events.

2.1

In Vivo Microdialysis

Microdialysis is one of the most commonly used methods for the in vivo detection of dopamine and has excellent analyte selectivity and sensitivity. In microdialysis, extracellular dialysates of the brain are sampled through a membrane that is permeable to water and small solutes (Bito et al. 1966). The inside of the microdialysis probe inserted into the brain region of interest is continuously flushed with an isomolar solution that lacks the analyte of interest. The analyte of interest is sampled after diffusion from the extracellular space across the membrane into the microdialysis probe and thus changes in concentration can be detected. Another variant of this technique used for determining the absolute basal analyte concentrations is no-net flux microdialysis, which involves perfusion of known concentrations of the analyte of interest through the probe to establish when an equilibrium between the inside and the outside of the probe is reached (Parsons and Justice 1992). Despite the considerable size of the microdialysis probe (0.2–0.5 mm in diameter; 1–2 mm working length), several experimental studies indicate that the damage to the blood–brain barrier is minimal (e.g., Westerink and De Vries 1988; Tossman and Ungerstedt 1986). Microdialysis is a sampling technique that is not directly coupled to any particular method of chemical analysis. The vast majority of studies uses high performance liquid chromatography in conjunction with electrochemical or fluorescence detection to analyze the very small amount of chemicals in the dialysate. Due to this small amount of dialysate, the sampling time-resolution is usually between 5 and 20 min. Even though there are now technical advances that will enable sample collection in intervals significantly shorter than a minute (Bowser and Kennedy 2001), most microdialysis experiments still operate on relatively low temporal resolution and are best suited for the quantitative analysis of basal and slowly changing tonic dopamine concentrations.

2.2

Electrochemical Techniques

It is known that dopamine neuron activity responds to reward-related stimuli on a subsecond timescale (Schultz et al. 1997). To fully understand control of behavior


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by dopamine in the NAcc and its role in drug addiction, we require neurochemical information with this level of temporal resolution. Electrophysiological recordings provide excellent temporal resolution but usually do not determine the projection target of recorded neurons, and thus cannot inform us on neurotransmission in specific terminal structures. In contrast, electrochemical or voltammetric techniques combine sampling of dopamine neurotransmission in specific terminal structures with excellent temporal resolution. Although various voltammetric methods have been developed over the years, the basic principle underlying each of these variations is the application of a modest electrical potential sufficient to drive electrolysis of the analyte of interest in brain extracellular fluid (Adams 1976; Stamford 1986; Kawagoe et al. 1993). The current produced by this electrolysis can be measured at the electrode and is proportional to the number of molecules undergoing oxidation, and therefore to the concentration of analyte at the electrode surface (Adams 1976; Stamford 1986; Kawagoe et al. 1993). Adams and coworkers pioneered voltammetric recordings of dopamine in the 1970s (Adams 1976). However, the presence of high concentrations of electroactive neurotransmitter metabolites, as well as ascorbic acid and uric acid, interfered with their recordings (Marsden et al. 1988). Technical advances such as the utilization of modified electrodes and more complex input voltage command waveform to improve selectivity (e.g., Gonon et al. 1981; Gonzalez-Mora et al. 1991) have led to the development of three predominant techniques for hightemporal resolution monitoring of dopamine using carbon-fiber microelectrodes: (a) amperometry, (b) high-speed chronoamperometry, and (c) FSCV (Garris and Rebec 2002). These techniques are now often referred to as voltammetric techniques. They are very attractive tools for chemical monitoring in the brain because measurements can be made with a small probe (5–30 mm in diameter; less than 200 mm working length) that causes minimal tissue damage and allows for sampling in precise brain areas. Considering the size of the carbon fiber electrode and the size of the synaptic cleft (15–25 nm; Savtchenko and Rusakov 2007), it is evident that voltammetry monitors the dopamine overflow in the extrasynaptic extracellular space and not dopamine in the synaptic cleft. Of these techniques, (constantpotential) amperometry is the fastest and “simplest” as it applies a continuous, constant potential to the electrode. Although this variant has microsecond temporal resolution, it offers little chemical selectivity since current produced by oxidation of any compound will be detected. Thus, amperometry is of great utility in studying, for example, fast release and uptake kinetics of single cells in brain slices (e.g., Chow et al. 1992), but has found little use in behaving animals. The remaining two techniques are reviewed below.

2.2.1

In Vivo Chronoamperometry

In chronoamperometric recordings, the potential of the working electrode is stepped up, held at this higher potential, and then stepped back down, while the resulting oxidation and reduction currents from faradic processes occurring at the

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electrode are monitored. Such currents have either been analyzed on the level of seconds (for simplicity here termed: high time resolution) or averaged to achieve a better signal-to-noise ratio with a time resolution of minutes to hours (low time resolution). Because electroactive species have different chemical reversibilities, a ratio of oxidation and reduction currents (redox ratios) can assist in identifying the primary substance contributing to changes in the electrochemical signal (e.g., Gratton et al. 1989). Chemical sensitivity is improved further in this technique by using electrodes coated with Nafion, an ion-selective polymer, (Gerhardt et al. 1984) that reduces the contribution of anionic species such as ascorbic acid and the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) to the signal. 2.2.2

In Vivo FSCV

Compared to chronoamperometry, FSCV is a more selective electrochemical method, because it utilizes a triangle input waveform (and not a step function) to separate electrolysis from different analytes into temporally resolved peaks in the output current. Since the voltage is swept gradually to an oxidizing potential and back, current is generated over time, during oxidation and reduction processes, whereby producing multiple electrochemical peaks for an ideal compound. This allows for the recording of a chemical signature, the voltammogram, that serves to identify the species detected, separating the signal from changes in pH and “other noise” and making the chemical resolution more robust (e.g., Baur et al. 1988, Michael et al. 1998). The voltammogram has sufficient information that it can be used with high-powered statistical analysis and provides standardized identification of the dopamine signal (Heien et al. 2004). For this chemometric approach, a socalled “training set” of phasic dopamine events of different amplitude spanning the concentration range of interest is collected (stimulated electrically with varying pulse rate and frequency). This training set is then used to perform a principal component analysis of the signal to statistically identify dopamine events.

3 Effects of Drugs of Abuse on Extracellular Dopamine Concentration in the NAcc 3.1

The Dopamine Hypothesis of Addiction

It has been proposed that the critical mechanism for the development of addiction is drug-induced activation of dopamine transmission in the NAcc, also referred to as the “dopamine hypothesis of addiction” (Fibiger et al. 1987; Wise and Bozarth 1987; Di Chiara and Imperato 1988). Electrophysiological studies have shown that acute exposure to many drugs of abuse affect the firing properties of dopamine neurons in the VTA despite their many distinct actions in the brain (for review, see Wanat et al. in press). However, to directly study dopamine signaling in the NAcc


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and to fully characterize the functions of dopamine in this target region, it is essential to study dopamine release into the extracellular space (discussed later) in addition to dopamine cell firing.

3.2

Drug Effects on Dopamine Signaling Measured Over the Course of Minutes: Microdialysis Studies

In the following sections, we will focus on studies investigating the effects of abused drugs on dopamine levels in the NAcc in freely moving animals. Microdialysis studies in behaving animals demonstrated that response-independent, systemic administration of cocaine, amphetamine, heroin, cannabinoids, nicotine, and ethanol increase dopamine levels in the NAcc (Di Chiara and Imperato 1986; Imperato and Di Chiara 1986; Imperato et al. 1986; Di Chiara and Imperato 1988; Kalivas and Duffy 1990; Kuczesnki et al. 1991; Yoshimoto et al. 1992; Pontieri et al. 1996; Tanda et al. 1997). The dose of the drug administered and the concentration of striatal dopamine following drug administration are positively correlated, as demonstrated for cocaine and ethanol (Nicolaysen et al. 1988; Bradberry 2002). Similar to response-independent drug administration, selfadministered drugs of abuse, including cocaine, amphetamine, heroin and ethanol, induce increases in concentrations of dopamine in the NAcc (Hurd et al. 1989, 1990; Pettit and Justice 1989, 1991; Weiss et al. 1992, 1993; Di Ciano et al. 1995; Wise et al. 1995a, b). Conversely, drugs with low potential for abuse do not affect dopamine overflow (Di Chiara and Imperato 1988). These findings are in agreement with the dopamine hypothesis of addiction (see Sect. 3.1), since drugs of abuse increase tonic concentrations of extracellular dopamine in the NAcc. During psychostimulant self-administration, animals learn to “load up” drug concentrations with an initial burst of operant responses before settling into a slower, more regular pattern of responding with inter-response rates varying between 2 and 20 min (Carelli and Deadwyler 1996). Response rates are inversely related to the infusion dose of cocaine or amphetamine; thus, the lower the dose the higher the number of responses (Pickens and Thompson 1968; Wilson et al. 1971; Yokel and Pickens 1973; Wise and Bozarth 1987; Di Ciano et al. 1995). However, the total intake of these drugs is elevated with higher doses. This intake pattern seems not to be due to aversive drug effects at high doses, since monkeys will choose infrequent high doses in preference to more frequent low doses (Iglauer et al. 1976) and rats show no reliable preference for one over the other (Di Ciano et al. 1995). Furthermore, animals will adjust their response rates to meet increased operant response demands (Roberts et al. 1989). Together, this suggests that animals titrate their drug intake to achieve a preferred level of intoxication. Cocaine-induced increases in extracellular NAcc dopamine concentrations are thought to be the principal neurochemical event associated with the drug’s positive reinforcing action (see Sect. 1.3; Kuhar et al. 1991; Wise and Bozarth 1987; Roberts et al. 1977; Ritz et al. 1987). For example, psychostimulants are self-administered

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directly into the NAcc (Hoebel et al. 1983; MCkinzie et al. 1999), and morphine and ethanol into the VTA (e.g., Bozarth and Wise 1981; Gatto et al. 1994). With increased drug dose the dopamine “maintenance” concentration in the NAcc is also held at an increased level (Pettit and Justice 1991). Importantly, microdialysis studies have shown that animals will maintain the increased NAcc dopamine concentration during cocaine, amphetamine, and heroin self-administration sessions at a steady level over days, just like they maintain the drug concentrations at a steady level (Pettit and Justice 1989; Pettit et al. 1990; Wise et al. 1995a, b; Ranaldi et al. 1999). Furthermore, in a microdialysis study with advanced temporal resolution that sampled dopamine every minute, Wise et al. (1995b) demonstrated that the selfadministration pattern of cocaine closely followed NAcc dopamine levels within sessions. This study demonstrated that cocaine dose-dependently increased dopamine concentrations after an infusion and that rats self-administered the next infusion as soon as the dopamine concentration diminished past a certain threshold. Consistent with this finding, it has been proposed that functional dopamine depletion in the NAcc represents a neurochemical correlate of drug craving (Dackis and Gold 1985; Koob et al. 1989). The findings presented above suggest that fluctuation in tonic dopamine concentration in the NAcc is a common denominator between different abused drugs that can regulate drug self-administration behavior.

3.3

Drug Effects on Dopamine Signaling Measured Over the Course of Seconds to Hours: Chronoamperometry Studies

In vivo chronoamperometry studies in the behaving animal have demonstrated that experimenter-administered ethanol, cocaine, and amphetamine increase extracellular concentrations of dopamine over the course of minutes to hours (Kiyatkin 1994; Di Ciano et al. 1998b; Sabeti et al. 2003). Similarly, self-administration of heroin and psychostimulants caused an increase in dopamine concentrations in the NAcc on this time scale (Gratton 1996; Di Ciano et al. 2001, 2002). Thus, chronoamperometry studies with low time resolution confirmed microdialysis findings on the basic effects of abused drugs on extracellular concentration of dopamine in the NAcc. To further investigate the temporal dynamics of dopamine signaling in animals self-administering drug, chronoamperometry with high time resolution was used to monitor dopamine on the order of seconds. NAcc dopamine concentrations were found to gradually increase preceding and to drop immediately following responsedependent (and -independent) intravenous injections of cocaine, before rising again around 4–6 min after infusion (Kiyatkin and Stein 1994, 1995). These postresponse decreases in signal were dose-dependent, absent when the infusion was withheld, and the preresponse increases became increasingly bigger when the access to the lever was blocked (Kiyatkin and Stein, 1993; Kiyatkin and Gratton 1994; Gratton 1996). Furthermore, chronoamperometry studies reported similar response patterns during operant behavior maintained by other reinforcers such as heroin


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(Kiyatkin and Stein 1993) and food (Kiyatkin and Gratton 1994), supporting the assumption that dopamine is the principal contributor to the reported biphasic signal fluctuations. In summary, the described high time resolution chronoamperometric data are in conflict with microdialysis findings which found that dopamine levels in the NAcc rise and fall in unison with oscillating blood/brain stimulant levels (Pettit and Justice 1989; Koob and Bloom 1988; Wise and Bozarth 1987; see Sect. 3.2). The validity of chronoamperometry measurements has been challenged on the basis of chemical sensitivity (Salamone 1996; Di Chiara 2002; Wightman and Robinson 2002). First, even though the electrodes are much less sensitive to DOPAC than to dopamine, the DOPAC concentration is several hundred times higher than dopamine and fluctuations in DOPAC concentration may contribute to the signal (Dayton et al. 1981; Gonon et al. 1984). Second, the voltage input step used to measure current changes that were assumed to be due to the oxidation/ reduction of dopamine also measures changes in pH that often accompany dopamine signaling (Heien et al. 2004). The argument that chemical species other than dopamine are contributing to the chronoamperometry signal is supported by the fact that the detected task-related signaling changed dramatically during the development of self-administration behavior (Gratton 1996), an observation not reported for heroin or by microdialysis studies with cocaine. Furthermore, chronoamperometry studies report drug-induced elevations in dopamine concentrations last nearly twice as long as that measured with microdialysis (Di Ciano et al. 1995). Although these results were replicated and the reported electrochemical changes were shown to be task-related, one cannot be sure about the chemical specificity of the signal (Wightman and Robinson 2002), especially in light of evidence from a microdialysis study reporting the opposite finding (Wise et al. 1995b; see Sect. 3.2). In summary, microdialysis and low time resolution chronoamperometry studies have convincingly demonstrated a link between tonic dopamine concentrations in the NAcc and the reinforcing effects of drugs of abuse. However, both techniques also raised questions. For example, what is the detailed temporal composition of dopamine signals? In contrast, chronoamperometry with high temporal resolution leaves the question of the chemical identity of observed phasic changes unanswered. These questions and some of the above described issues are not resolvable with these techniques, as the need for a combination of high temporal and chemical resolution is not satisfied by either of these techniques alone.

3.4

3.4.1

Drug Effects on Dopamine Signaling Measured on a Subsecond Time Scale: FSCV Studies Changes in Phasic Dopamine Signaling to Response-Independent Drug Administration

FSCV provides sufficient temporal and chemical resolution to study phasic dopamine signals. For example, a single phasic dopamine event in response to either

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electrical stimulation or presentation of a salient stimulus can be assessed. Furthermore, FSCV can examine the effects of drugs of abuse on phasic dopamine in both in vitro (slice) and in vivo (anesthetized, awake, and during self-administration) preparations, and can separate dopamine release and uptake. In addition to the amplitude and duration of phasic dopamine changes, the frequency of “spontaneous” dopamine transients (i.e., phasic release events found in the awake animal that are not attributed to specific events in the animal’s environment) can also be measured. Thus, findings obtained with FSCV illustrate a greater complexity of dopamine signaling than previously described by data from other techniques (see Sects. 3.2 and 3.3). The phasic NAcc dopamine response to ethanol and cannabinoids illustrates the complexity in the profile of subsecond dopamine signaling. Ethanol showed no effect on dopamine uptake in striatal brain slices collected from drug-naı¨ve rats (Samson et al. 1997; Budygin et al. 2001b; Mathews et al. 2006), but enhanced dopamine uptake in animals chronically treated with ethanol, possibly due to a compensatory mechanism resulting from elevated dopamine levels (Budygin et al. 2007). Consistent with this, both ethanol and cannabinoids attenuate electrically stimulated dopamine release in the intact animal, possibly due to increased tonic dopamine levels (see Sect. 3.2) that impair phasic dopamine release due to activation of release-regulating autoreceptors (Budygin et al. 2001a; Cheer et al. 2004). In contrast, intravenous infusions of ethanol and cannabinoids increased the amplitude and/or frequency of spontaneous phasic dopamine transients in awake, behaving animals (Cheer et al. 2004, 2007). These findings suggest that the complexity conferred by multiple mechanisms make it difficult to parsimoniously use findings from in vitro preparations and artificial electrical stimulations to make net predictions concerning the effect of drugs on phasic dopamine signaling in awake, behaving rodents. In agreement with results presented in Sect. 3.2 that indicated enhanced tonic dopamine concentrations in the NAcc, the findings presented above demonstrate increased frequency of spontaneous phasic dopamine signals by ethanol and cannabinoids. A number of FSCV studies have examined the effect of nicotine on phasic dopamine release in both in vitro and in vivo preparations. In contrast to ethanol, acute in vivo nicotine exposure enhances dopamine uptake in the striatum of the anesthetized rat (Middleton et al. 2004). Nicotine exerts frequency-dependent effects on electrically stimulated phasic dopamine release in vitro; at low firing rates dopamine release is attenuated, but at high firing rates nicotine enhances dopamine release (Zhang and Sulzer 2004). Intravenous infusions of nicotine also increase the frequency and amplitude of spontaneous phasic dopamine release events in the behaving rat (Cheer et al. 2007). Together, both in vitro and in vivo studies consistently show enhanced phasic dopamine signaling in response to nicotine. Consistent with findings from other abused substances, intravenous infusions of cocaine increase amplitude and frequency of spontaneous phasic dopamine release events in the NAcc (Heien et al. 2005; Stuber et al. 2005a, b; Cheer et al. 2007; Wightman et al. 2007; Aragona et al. 2008), as well as the amplitude of electrically


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stimulated release (Wu et al. 2001). An increase in amplitude can be explained by decreased reuptake due to the pharmacological action of cocaine. However, it is not clear why cocaine increases the frequency of dopamine release events. It seems likely that more phasic signals exceed the FSCV detection threshold due to their increased amplitude and thus become “visible” under drug exposure. Another explanation is that drug-induced behavioral hyperactivity may stimulate afferents to the VTA, and therefore may increase the firing frequency of dopamine neurons projecting to the NAcc. Notably, these findings indicate that the strong increases in tonic dopamine levels described in Sect. 3.2 do not appear to result in significant autoreceptor-mediated inhibition of dopamine neurons; thus, one could describe the phasic signals as “riding on a tonic dopamine wave” during drug exposure. Interestingly, endogenous cannabinoids modulate the cocaine-, nicotine-, and ethanol-mediated increases in phasic dopamine release, as the effects of drugs on phasic dopamine release are attenuated by systemic cannabinoid receptor antagonism (Cheer et al. 2007). While the locus of this effect is yet to be determined, it is speculated that cannabinoid receptor activation in the VTA reduces GABA release on dopamine neurons (Riegel and Lupica 2004). These findings suggest that abused drugs exert similar effects on phasic dopamine release even though their respective pharmacological and cellular effects are quite distinct.

3.4.2

Changes in Phasic Dopamine Signaling During Cocaine Self-Administration: The Role of Operant Behavior and Conditioned Stimuli

Pavlovian and operant conditioning paradigms using nondrug reinforcers have demonstrated that conditioned stimuli (CS) can elicit phasic dopamine release (Roitman et al. 2004; Day et al. 2007; Stuber et al. 2008; Owesson-White et al. 2008). In studies using drug reinforcers, it has been shown that repeated CS presentation with drug delivery subsequently can elicit an electrochemical response when the CS is presented alone (Kiyatkin and Stein, 1993; Kiyatkin and Gratton 1994; Di Ciano et al. 1998a). This response develops over time, as its development requires at least 10–50 pairings of the drug with the CS (Gratton 1996), and therefore indicates that these dopamine signals reflect a learning process. Studies that probed the contribution of CS to phasic dopamine in response to drug taking will be discussed below. Contingent and noncontingent cocaine administration produce differential longterm effects on synaptic plasticity in VTA dopamine neurons (Chen et al. 2008). The effect of cocaine infusions on phasic dopamine release also depends on whether the drug administration is contingent upon an operant response or not, as shown with FSCV (Stuber et al. 2005a). For example, in rats pressing a lever for an intravenous infusion of cocaine, rapid changes in dopamine concentrations are time-locked to specific aspects of this behavior (Phillips et al. 2003; Stuber et al. 2005a, b; Fig. 1a), whereas no changes in dopamine levels are observed within 10 s of a responseindependent cocaine administration to awake, but idle rats (Stuber et al. 2005a).

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In contrast, following these initial 10 s, the frequency of spontaneous dopamine transients increases dramatically independent of whether the administration of the drug was response-independent or -dependent (Stuber et al. 2005a). However, there is an ongoing debate regarding the exact latency of the pharmacological effects of cocaine after intravenous infusion (Espana et al. 2008; Wise et al. 2008). The considerable variance in the onset of these transients may be due to variability in the latency of drug delivery to the brain. Together, this suggests that (a) early dopamine release events (first 10 s) in animals that self-administered cocaine may be related to learned associations and (b) the increase in spontaneous dopamine transients 10 s after the beginning of the infusion may be a consequence of the pharmacological effects of cocaine that are not related to learning. Consistent with this idea, these latter spontaneous transients are correlated with cocaine levels and the animal’s locomotion (Stuber et al. 2005a). In summary, cocaine self-administration is accompanied by early phasic dopamine release that is time-locked to the onset of drug infusion but cannot be attributed to the pharmacological effects of the drug. Phillips et al. (2003) demonstrated that the largest change in dopamine concentration time-locked to cocaine self-administration behavior occurs immediately upon completion of the operant response (Fig. 1a). This effect was conditioned to an audiovisual stimulus (presented on the completion of the lever response) and was not due to the pharmacological actions of cocaine since it persisted during initial extinction trials where cocaine is replaced with saline (Stuber et al. 2005b; Fig. 1b). If the CS denoting the onset of the cocaine infusion was presented noncontingently during the period between operant responses, a similar dopamine signal could be evoked. Furthermore, this signal diminished gradually when the associative strength between the stimuli and cocaine is weakened during extinction (Stuber et al. 2005b; Fig. 1b). This phenomenon is identical to what has been observed with nondrug reinforcers, where cues that predict availability of these reinforcers are able to elicit phasic dopamine release on their own (Roitman et al. 2004, OwessonWhite et al. 2008). Therefore, the change in extracellular dopamine that occurs at completion of the operant response (Fig. 1a) may encode the association of cue and drug delivery, and thus the expectation of cocaine delivery. Phasic dopamine release has also been demonstrated just prior to the operant response for a self-administered infusion of cocaine (Phillips et al. 2003, Stuber et al. 2005a, b; Fig. 1a). These changes tended to be smaller than those following the operant response, but consistently preceded the animal’s approach to the response lever. In agreement with these antecedent neurochemical signals, dopamine neuron activation also occurs immediately before subsequent injections in rats trained to bar press for intravenous heroin (Kiyatkin and Rebec 2001). Furthermore, chronoamperometric studies detected a slow increase in dopamine-related signals (over the course of multiple seconds) in rats before they approached the lever for the next drug self-administration (Kiyatkin and Stein 1995). This temporal correlation with the drug seeking (lever approach) suggests that this component of the neurochemical signal might be causally linked to the behavior (Phillips et al. 2003, Stuber et al. 2005a, b). The temporal proximity of the signal precludes testing its role in drug seeking using conventional pharmacological approaches, since blockade of


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a

drug selfadministration infusion (maintenance) cue

1 2

3 3 3

6s 20 s

b

extinction

time cue lever press

lever press

lever press

Fig. 1 Phasic dopamine signaling in the NAcc associated with drug seeking and taking. (a) Phasic dopamine signaling consists of multiple phasic events (triangles). The first event is elicited by the animal’s approach of the operant lever (preresponse signal) (1), whereas a bigger second event is associated with the onset of the audiovisual cue (dark gray bar) that is presented in response to the lever press (postresponse signal) (2). A set of peaks (3) that is observed with an onset of approximately 10 s after the lever press and the beginning of the drug infusion (light gray bar), is thought to be a direct consequence of the pharmacological effect of the drug. The latency of this pharmacological effect relative to the operant response appears to be more variable than for the postresponse signal. (b) During extinction, the audiovisual stimulus presented after the lever press is not accompanied by a drug infusion. As a consequence, the postresponse dopamine signal becomes smaller with repeated nonreinforced responding. In contrast, the preresponse signal remains relatively stable during extinction. This suggests that the preresponse signal reflects the motivation to obtain drug, whereas the postresponse encodes the expectation of the drug infusion

this signal will perturb other phasic dopamine signals or the tonic baseline level of dopamine. However, an electrically evoked dopamine signal of similar brevity was sufficient to promote the lever approach (drug seeking), as such brief changes in dopamine, heavily influenced drug seeking by biasing the animal to initiate this behavior (Phillips et al. 2003). This may indicate a role for phasic dopamine in drug seeking or at least biasing the animal’s decision-making policies towards selecting actions leading to drug taking, rather than a direct role in drug reward. In contrast to the postresponse signal, this preresponse signal does not appear to be a learned or conditioned process because it does not disappear during extinction trials, where the CS was presented contingent to the operant response but without drug infusion (Stuber et al. 2005b; Fig. 1b). Together, these findings indicate that the preresponse dopamine signal may be involved in initiating approach behavior. In summary, these findings underline the multiple roles of phasic dopamine in operant responding for cocaine. Phasic dopamine release associated with operant behavior is comprised of signals in relation to approach, conditioned cues, and the

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pharmacological effects of the drug (Fig. 1a). Dopamine signaling is likely to play a role in motivation, but probably also encodes other information about goal-directed behavior including learned association between cues and drug reward. The extinction-resistant preresponse signal seems to be related to drug seeking, and therefore may have a motivational quality. In contrast, the postresponse signal is linked to a learned association (lever-press and cue signaling the drug infusion), and therefore may be related to the expectation of drug delivery (see Sect. 3.4.2). Compared to natural reinforcers, such behavior-related dopamine release is enhanced due to the pharmacological properties of abused drugs. Therefore, the normal function of these signals is potentially corrupted, which may explain dysregulated goaldirected behavior in addiction (see Sect. 7.2).

3.5

Summary

The findings obtained in FSCV studies examining the effects of different drugs of abuse on phasic dopamine signaling in the NAcc are in general agreement with findings made with microdialysis and low time resolution chronoamperometry (see Sects. 3.2 and 3.3), as each of these techniques have shown that response-dependent and -independent administration of abused drugs increase dopamine levels in the NAcc. Thus, both phasic and tonic concentrations of dopamine in the NAcc are enhanced by drugs, which is in agreement with the postulate of the dopamine hypothesis of addiction that drugs of abuse converge on the mesolimbic dopamine pathway. These findings also raise the question as to what extent such phasic events contribute to the observed changes in tonic dopamine levels. Some evidence indicates that spontaneous dopamine transients that presumably reflect the pharmacological effects of drugs are likely to alter overall tonic dopamine concentrations (see Sect. 3.4.2). Future studies are required to investigate a possible interaction between phasic and tonic dopamine signaling and to examine phasic dopamine release during the self-administration of a wider range of abused substances.

4 Effects of Withdrawal from Drugs of Abuse on the NAcc Dopamine System While the acute effects of drugs on the dopamine system are well cataloged, the long-term effects after cessation of drug intake are less well studied and understood. This disconnection in the research is partly because the latter effects show considerable variance that arises from the drug studied, how the drug is administered (dose, frequency, and route), and duration of abstinence after drug experience (Wanat et al. in press). It has been documented that repeated exposure to a drug of abuse causes structural changes in VTA dopamine neurons, as repeated opiate


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exposure decreases the size and caliber of dendrites and soma of VTA dopamine neurons (Sklair-Tavron et al. 1996). Along with such structural changes, many studies support the notion that multiple drug exposures lead to an altered function of the dopamine system (Koob and Le Moal 2008), though the timing of this effect can vary.

4.1

Tonic Dopamine During Withdrawal

Microdialysis studies have demonstrated that the discontinuation of chronic treatment with ethanol (Rossetti et al. 1991, 1992a, b; Diana et al. 1993; Weiss et al. 1996), morphine (Acquas et al. 1991; Pothos et al. 1991; Acquas and Di Chiara 1992; Rossetti et al. 1992a, b; Crippens and Robinson 1994), nicotine (Rahman et al. 2004), amphetamine (Rossetti et al. 1992a), or cocaine (Parsons et al. 1991; Robertson et al. 1991; Imperato et al. 1992; Rossetti et al. 1992a, b; Segal and Kuczenski 1992; Weiss et al. 1992; Diana et al. 1993; Chefer and Shippenberg 2002; Zhang et al. 2003) decreases the basal extracellular concentration of dopamine in the NAcc. However, there have been conflicting reports for withdrawal from psychostimulants. For example, several studies demonstrated a lack of change in basal concentrations of NAcc dopamine after withdrawal from amphetamine (Segal and Kuczenski 1992; Crippens et al. 1993; Crippens and Robinson 1994; Paulson and Robinson 1996). In the case of cocaine, some studies reported that withdrawal does not change tonic NAcc dopamine (Robinson et al. 1988; Kalivas and Duffy 1993; Hooks et al. 1994; Meil et al. 1995; Kuczenski et al. 1997), and yet others found an increase in basal dopamine levels (Imperato et al. 1992; Weiss et al. 1992; Johnson and Glick 1993; Heidbreder et al. 1996). While some studies reported changes in basal dopamine levels depending upon the time of cocaine withdrawal (Imperato et al. 1992; Heidbreder et al. 1996), these observed changes have not been consistent across studies. For example, some report that withdrawal after chronic cocaine exposure decreases basal dopamine levels in as early as a few hours (Zhang et al. 2003) to as long as 10 days (Parsons et al. 1991), while others found increases in basal dopamine levels during 1–4 days of withdrawal (Imperato et al. 1992; Weiss et al. 1992; Heidbreder et al. 1996), and it was reported to have no effect on basal dopamine levels after 24 h and 2 weeks withdrawal (Kalivas and Duffy 1993; Meil et al. 1995). Thus, at least for cocaine, no clear temporal effect of withdrawal on basal dopamine levels can be inferred from these studies. The studies described above utilized either conventional microdialysis or the more accurate method of determining exact basal dopamine levels, no-net flux microdialysis (Parsons and Justice 1992). The majority of studies employing no-net flux microdialysis did not observe changes in dopamine levels after withdrawal from cocaine treatment, strongly supporting no or minor effects of cocaine withdrawal on tonic dopamine concentration (Crippens et al. 1993; Kalivas and Duffy 1993; Heidbreder et al. 1996; Chefer and Shippenberg 2002).

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Together, the effects of withdrawal from chronic drug treatment on NAcc dopamine levels depend on many factors, including the drug studied and the dose of the drug administered during the chronic treatment (Kalivas and Duffy 1993). In addition, it is known that tonic dopamine levels in the NAcc are affected by drug cues (see Sect. 5.1) and by contextual cues associated with aversive stimuli (Mark et al. 1991; Saulskaya and Marsden 1995). Re-exposure to a drug-paired environment can either be rewarding or aversive depending on drug dose and time of drug-cue pairing after drug administration (Ettenberg 2004). Differences in these parameters may explain some of the discrepancies between studies presented here. In summary, according to microdialysis studies the NAcc dopamine system may undergo a depression after withdrawal from abused substances; however, this finding remains controversial regarding psychostimulants such as cocaine.

4.2

Phasic Dopamine During (Short-Term) Withdrawal

Only one study using FSCV has examined how phasic dopamine release associated with drug taking is affected by withdrawal from drug self-administration. Stuber et al. (2005b) showed that the dopamine postresponse signal associated with the completion of the operant response gradually decreases during an extinction session immediately after completion of a cocaine self-administration session, whereas the preresponse signal remained relatively stable (Fig. 1b). Thus, the overall phasic dopamine release associated with the operant response for drug delivery decreases during withdrawal. However, this study does not reveal how phasic dopamine signals are affected by long-term withdrawal. Furthermore, the self-administration behavior underwent extinction instead of abstinence, a better model for the human condition because humans do not usually undergo extinction during drug withdrawal. The term “abstinence” will be used here to describe withdrawal from drug taking without extinction of drug taking behavior. We are aware of the fact that this term is not an ideal description of animal behavior since the animal does not refrain from drug taking voluntarily. Future studies should investigate changes in phasic dopamine signaling during long-term withdrawal after extinction or abstinence from drug taking. Collectively, these studies suggest that acute exposure to drugs of abuse activates phasic and tonic dopamine signaling in the NAcc (see Sect. 3), but withdrawal from chronic drug exposure can dampen phasic and tonic dopamine levels in the absence of drug (see Sect. 4). However, withdrawal from psychostimulants does not necessarily lead to decreased tonic levels. Decreased tonic levels of dopamine in the NAcc and firing of VTA dopamine neurons during drug withdrawal have been shown to return to and above basal levels by a subsequent drug re-exposure with ethanol (Diana et al. 1993; Weiss et al. 1996), amphetamine (Robinson et al. 1988), cocaine (Pettit et al. 1990), and morphine (Sklair-Tavron et al. 1996; Diana et al. 1999). Similarly, the extinction-induced decrease of the phasic postresponse dopamine signal can be reversed to previous amplitudes during a drug-induced


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reinstatement session, as shown by FSCV (Stuber et al. 2005b). Returning dampened dopamine levels to “baseline” may be one of the driving forces in relapse to drug taking behavior, since evidence presented in Sect. 3.2 indicates that animals pursue the next drug infusion when tonic dopamine levels in the NAcc decrease past a certain threshold.

5 Stimulus-Induced NAcc Dopamine Release in the Absence of Drug: Implications for Reinstatement of Drug Seeking 5.1

Effects of Drug Cues on Tonic Dopamine Concentration in the NAcc

In the previous sections, we reviewed the powerful effects of abused drugs on dopamine signaling in the NAcc during drug taking and withdrawal. This leads to the question of whether the NAcc dopamine system is also involved in reinstatement of drug seeking behavior after abstinence or extinction of drug taking. Re-exposure to drugs of abuse on a single occasion can promote relapse to drug seeking behavior in abstinent human drug users (Jaffe et al. 1989). Similarly, exposure to a CS associated with self-administered drugs can elicit subjective states such as craving (Grant et al. 1996; Childress et al. 1999; Garavan et al. 2000), as well as drug seeking and relapse in humans (Stewart et al. 1984; Avants et al. 1995) and experimental animals (Markou et al. 1993, Robinson and Berridge 1993). Furthermore, even after extinction of self-administration behavior, drug seeking can be reinstated in animals by presentation of conditioned drug cues (e.g., de Wit and Stewart 1981; Weiss et al. 2000). It has been proposed that the ability of conditioned drug cues to increase dopamine is critical for reinstatement of drug seeking (Stewart et al. 1984), and support for this assumption is provided by findings in animals (see Sect. 3.4.2). Further evidence for the involvement of NAcc dopamine signaling in drug-induced reinstatement is provided by findings demonstrating that microinjection of amphetamine into the NAcc can reinstate heroin self-administration (Stewart and Vezina 1988) and that such drug seeking can be attenuated by drugs that decrease dopamine neuron activity (Di Ciano and Everitt 2003, 2004; Bossert et al. 2004). In contrast, a decrease in the concentration of extracellular dopamine in the NAcc may contribute to some drug withdrawal symptoms (Rossetti et al. 1992b). Decreasing withdrawal symptoms by increasing dopamine levels may therefore possibly promote the motivation to reinstate drug taking (Koob and Le Moal 2008). Therefore, we will now focus on studies examining drug cue-induced changes in dopamine release and how this relates to reinstatement of drug seeking. Several studies have observed increases in tonic dopamine concentrations in the NAcc following the noncontingent presentation of a psychostimulant-paired CS in the absence of drug. Such CS-induced effects were demonstrated after pairing of

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the CS with response-independent (Fontana et al. 1993; Di Ciano et al. 1998b) as well as with response-dependent (Gratton and Wise 1994; Kiyatkin and Stein 1996; Di Ciano et al. 1998a; Ito et al. 2000) drug administration. Similar conditioned changes in dopamine have been shown in the NAcc following the noncontingent presentation of stimuli previously paired with food (Young et al. 1998), heroin (Gratton 1996), or footshock (Wilkinson et al. 1998). In contrast to noncontingent presentation, response-contingent presentation of a CS failed to produce changes in tonic NAcc dopamine (Neisewander et al. 1996; Ito et al. 2000). In fact, one study found no difference in NAcc dopamine concentrations during cocaine self-administration without concurrent presentation of the CS as compared to self-administration of cocaine plus contingent presentation of a CS (Bradberry et al. 2000). However, it should be noted that other studies have found no change in tonic dopamine efflux in response to the noncontingent presentation of drug cues (Brown and Fibiger 1992; Bradberry et al. 2000). This discrepancy may be due to the proximity of changes in dopamine concentrations to the microdialysis detection limit, where minor differences in the study design, for example, the number of stimulus-reward pairings or CS presentations, may cause different outcomes. Overall, these findings suggest that noncontingent (but not contingent) presentation of drug-paired cues can contribute to overall changes in tonic NAcc dopamine. Few studies have examined dopamine release during actual cue-induced reinstatement of drug-seeking after abstinence or extinction of the operant behavior. One study found elevations in tonic NAcc dopamine after extinction in conjunction with robust cocaine-seeking behavior elicited by sustained (60 min) presentation of a salient discriminate stimulus that previously signaled the availability of cocaine (Weiss et al. 2000). In contrast, reinstatement elicited by brief noncontingent presentation of a visual drug cue during or after extinction did not produce significant changes in dopamine efflux, although drug-induced reinstatement showed both a behavioral and a neurochemical response (Neisewander et al. 1996; Di Ciano et al. 2001). This suggests that repeated or sustained noncontingent presentation of drug-associated cues may be necessary to elicit changes in tonic dopamine concentrations during reinstatement of drug seeking that are detectable with microdialysis.

5.2

Effects of Drug Cues on Phasic Dopamine Signaling in the NAcc

There are no studies to date that have examined cue-induced reinstatement of drug seeking with FSCV. However, Stuber et al. (2005b) demonstrated that the phasic dopamine component that occurs following a lever-press for cocaine infusion (postresponse) gradually diminishes during extinction, whereas the signal that occurs just prior to the lever-press (preresponse) seems resistant to extinction (Fig. 1b, see Sect. 4.2). During drug-induced reinstatement, postresponse but phasic dopamine release returns to the previous pre-extinction amplitude, suggesting that


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it encodes a learned association between cue and drug delivery (Stuber et al. 2005b). In addition, studies recording neuronal firing in the NAcc during withinsession extinction have shown that neurons with a postresponse discharge pattern are less active during extinction and return their activity to pre-extinction levels after reinstatement (Carelli and Ijames 2000). The absence of the postresponse signal after extinction in both striatal dopamine release and NAcc cell firing makes it an unlikely candidate as the driving force behind the initiation of the reinstatement of drug seeking. Moreover, the increase in postresponse dopamine does not cause further cocaine seeking in self-administration maintenance sessions, as it would be expected if this aspect of the dopamine signal is involved in approach behavior or drug seeking. Instead the animals typically engage in stereotypies during the immediate postresponse phase before seeking the next infusion (Stuber et al. 2005a). However, abstinent human addicts generally do not undergo extinction, and thus drug cues may retain their capacity to elicit dopamine release. Furthermore, the postresponse signal may reappear during subsequent extinction sessions, as drug seeking in response to drug cues is not permanently extinguished after a single extinction session, as shown in many studies (Shalev et al. 2002). In contrast to the postresponse dopamine signal, the preresponse dopamine signal may be an essential component of reinstatement of drug seeking since it remains relatively stable during extinction (Fig. 1b), and an electrically evoked dopamine signal of similar brevity is sufficient to induce drug seeking (Phillips et al. 2003). Additionally, animals will approach and press a lever for an infusion of dopamine into the NAcc (Dworkin et al. 1986). Such a dopamine-induced approach response may be more reliably triggered in a drug-related environment where the approach is directed towards a familiar goal. Together, the findings presented in Sects. 5.1 and 5.2 indicate that tonic and phasic dopamine concentrations in the NAcc can be increased during (noncontingent) cue-induced reinstatement of drug seeking. However, there have been few studies of this effect and their findings are somewhat inconsistent, which may reflect the highly dynamic quality of the phasic dopamine postresponse that fades quickly under extinction conditions. The lack of reinstatement-related tonic dopamine changes after brief exposure to drug cues under extinction conditions may thus be attributable to a diminished amount of phasic dopamine per lever approach (decreased postresponse dopamine), whereas higher tonic dopamine levels can be achieved with sustained cue exposure. These findings suggest that the more stable preresponse component of the dopamine signal (Fig. 1b) may be of greater significance in eliciting reinstatement of drug seeking.

6 The Role of NAcc Dopamine in Drug Addiction Altered dopamine signaling has been implicated in all stages of drug addiction, from induction to maintenance to relapse. Unlike natural reinforcers, drugs act directly on the mesolimbic dopamine system thereby bypassing sensory processing and

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adaptive mechanisms that normally control NAcc dopamine release. Most theories of drug addiction postulate that this “direct access” to dopamine signaling results in abnormal shaping of synaptic efficiency. However, addiction theories differ regarding the effect that these processes have on the organism (discussed later).

6.1

Motivation and Addiction

The “incentive-sensitization” theory of addiction proposed by Robinson and Berridge (1993) emphasizes the motivational function of NAcc dopamine. It states that hedonic processes (“liking”) associated with drug intake are not mediated by the mesolimbic dopamine projection, which instead is involved in the attribution of incentive salience to stimuli associated with rewards (“wanting”) (as described in Sect. 1.5.1). Thus, this theory postulates that NAcc dopamine mediates the motivation to pursue rewards. Addictive drugs are assumed to render these brain reward systems hypersensitive (i.e., “sensitized”) to drugs and drug-related stimuli, causing pathological wanting of drugs. According to this view, relapse to drug seeking and compulsive aspects of drug taking are mediated by the sensitized dopamine efflux in the NAcc in response to a drug-paired CS.

6.2

Associative Learning and Addiction

Dopamine receptors regulate intracellular signaling cascades that alter the expression of genes, such as immediate-early genes, which are considered to be one of the first molecular steps that ultimately result in stable neuroadaptations and behavioral changes (for review, see Davis and Squire 1984; Stork and Welzl 1999; Tischmeyer and Grimm 1999). In the striatum, such mechanisms have been shown to play a central role in learning-related changes in protein synthesis (Teather et al. 2005; Hernandez et al. 2006). Consistent with associative learning theories of addiction, psychostimulants engage a set of molecular mechanisms normally implicated in learning and memory including D1 receptors and downstream intracellular messenger cascades that may cause synaptic rearrangements (Berke and Hyman 2000; Everitt et al. 2001). Thus, psychostimulant-induced dopamine release may alter learning-related molecular changes by activating common signal transduction pathways. In fact, the effects of psychostimulants on procedural memory consolidation have been demonstrated in many studies (e.g., Puglisi-Allegra et al. 1994; Castellano et al. 1996; Cestari and Castellano 1996; Packard and White 1991). Importantly, recent studies found D1 receptor-dependent effects of cocaine on procedural learning in association with molecular changes in the striatum (Willuhn and Steiner 2006, 2008). A current influential hypothesis that incorporates these findings would suggest that addiction is due to drug-induced neuroadaptations in reward-related learning and memory processes in the NAcc (Berke and Hyman 2000; Everitt et al. 2001). Such neuroadaptations are believed to cause


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hypersensitivity to cocaine-associated cues (Di Chiara and Bassareo 2007; Everitt and Wolf 2002) and abnormal habit-like behaviors (White 1996) that become insensitive to adverse consequences with chronic drug exposure and lead to compulsive drug intake (Wolffgramm and Heyne 1995; Deroche-Gamonet et al. 2004).

7 Different Functions for Phasic and Tonic Dopamine Transmission in Addiction How can the different modes of dopamine transmission, phasic and tonic signaling, be synthesized with different theories of addiction? Most experiments do not distinguish between these two modes of neurotransmission. For example, in vivo microdialysis and low time resolution chronoamperometry measure changes in tonic levels of dopamine, but it is not clear how much phasic signaling contributes to tonic extracellular concentrations of dopamine, and, thus, these techniques potentially measure the sum of both tonic and phasic dopamine. Similarly, pharmacological manipulations of the dopamine system modify both tonic and phasic aspects of dopamine neurotransmission, as both modes presumably utilize the same mechanisms of release and reuptake. Interestingly, it is both experimentally and conceptually challenging to separate the different functions of dopamine on a behavioral level. As described in Sect. 1.5, dopamine signaling is thought to be implicated in both reinforcement learning and motivation. Dopamine is thought to facilitate reinforcement learning by “stamping in” stimulus-reward associations (Wise 2004), providing a prediction error (Montague et al. 2004), and/or by biasing action selection (Redgrave and Gurney 2006). Alternatively, dopamine is thought to facilitate motivation by enhancing the energizing effect of reward or rewardpredicting cues through assignment of incentive salience (Robinson and Berridge 1993, 2008) and/or by maintaining behavior when response costs are high (Salamone and Correa 2002). Later, we argue that the different temporal modes of dopamine signaling fulfill both learning and motivational functions. Recent research, using a genetic approach, indicates that phasic and tonic dopamine signaling may indeed subserve different functions. Specifically, reduced expression of the dopamine transporter in the striatum and thus reduced clearance of released dopamine has been shown to cause increased motivation in a previously learned task in the absence of new learning (Cagniard et al. 2006b). Importantly, mice carrying this inducible knockdown of the dopamine transporter showed increased nonbursting activity of dopamine neurons (presumably driving tonic dopamine concentration in the striatum) but no change in burst firing (presumably driving phasic dopamine release). Thus, these mice learned a behavioral task and were then rendered tonically hyperdopaminergic, which led to a better performance in this task without affecting reinforcement learning subsequently tested in another task (Cagniard et al. 2006b). This important finding suggests that tonic dopamine signaling may mediate motivational aspects of behavior. Conversely, it has been suggested that phasic signaling is particularly well suited for transmitting rapid

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time-specific information and thus provide the temporal resolution necessary to represent the contingencies in reinforcement learning (Grace 1991; Schultz 2007). FSCV recordings in the NAcc were made from rats during Pavlovian reinforcement learning support this role for phasic dopamine release (Day et al. 2007; Sunsay and Rebec 2008; Stuber et al. 2008). Early in training, phasic dopamine responses are observed primarily with reward delivery (unconditioned stimulus, US). With continued training, dopamine release is elicited by the presentation of the CS, while the response to the US is attenuated, suggesting a transfer of the phasic dopamine response from the US to the CS (Day et al. 2007; Sunsay and Rebec 2008). Such a role for dopamine in the learning of stimulus–reward associations has also been demonstrated in electrophysiological studies (Schultz et al. 1997; see Sect. 1.5.2) and cocaine self-administration studies using FSCV, as discussed in Sect. 3.4.2 (Phillips et al. 2003; Stuber et al. 2005a, b). However, phasic dopamine is also associated with initiating goal-directed behaviors, and thus may have a motivational impact as well (see Sect. 3.4.2; Phillips et al. 2003). Therefore, phasic signaling, time-locked to drug intake and drug-predicting stimuli, may contribute to both the motivational aspects of drug taking and associative learning related to drug taking. Together, these findings suggest that different time scales of dopamine transmission may have different functions, where different aspects of phasic signaling is related to both reinforcement learning and approach behavior (motivation), and tonic signaling enables motivational and motor systems but not reinforcement learning.

7.1

Dopamine Signaling in the Drug-Naı¨ve State (Fig. 2a)

In Fig. 2, we summarize data reviewed in this chapter in a simplified manner and discuss it in light of the theoretical framework of NAcc dopamine function reviewed in Sects. 1.5 and 6. In a drug-naı¨ve state (Fig. 2a), it is assumed that NAcc neurons receive physiological levels of receptor stimulation by tonic dopamine release providing normal motivational function of the organism. Phasic dopamine release and subsequent postsynaptic dopamine receptor stimulation may alter synaptic plasticity on striatal projection neurons (in concert with glutamate signals) in response to behaviorally relevant novel stimuli and natural reinforcers. Together this allows for normal goal-directed behavior and reinforcement learning. In this drug-naı¨ve state (Fig. 2a), stimuli that are specifically associated with drug intake, such as drug paraphernalia or cues predicting drug availability, will not affect dopamine neuron firing or release because the organism has not yet been exposed to the drug.

7.2

Immediate Effects of Drug Exposure (Fig. 2b)

Thus far, we have reviewed data demonstrating that acute exposure to drugs of abuse increases phasic (see Sect. 3.4) and tonic dopamine concentrations (see


a

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phasic baseline tonic

drug-naive

b

during drug exposure

c withdrawal (drug-free) non-drug cue

no cue

drug cue

Fig. 2 Drug-induced changes in phasic and tonic dopamine transmission in the NAcc. (a) In the drug-naı¨ve state, phasic (triangles) and tonic (solid horizontal line) dopamine signaling in the NAcc is normal. Few spontaneous phasic dopamine events (no cue) are observed. Salient stimuli (nondrug cues) can elicit phasic dopamine release and goal-directed behavior. (b) Drugs of abuse enhance tonic (dashed line) and phasic (triangles) dopamine signaling. Stimuli not associated with drug (nondrug cues) and drug-related cues both elicit phasic dopamine events, but the latter cause more robust release due to the temporal proximity to the drug administration. Furthermore, the number of spontaneous phasic dopamine events is increased. This may lead to aberrant learning of drug-cue associations and thus abnormal goal-directed behavior such as compulsive drug taking. (c) Effects of drug withdrawal on dopamine signaling are variable. For example, dampened tonic dopamine concentrations during withdrawal can be returned to and above basal concentrations by exposure to drug cues and drug context (left to right). Such drug cues may also elicit more phasic dopamine release (dashed triangle) compared to nondrug cues because (1) drugs represent a higher reward magnitude than natural reinforcers and/or (2) extended withdrawal results in incubation of drug craving. As a consequence, independent of tonic dopamine levels, seeking for drugs is more prevalent than seeking for natural reinforcers, which may promote relapse to drug taking

Sect. 3.2 and 3.3) in the NAcc. What are the potential behavioral consequences of this enhanced dopamine signaling? During drug exposure, cues predicting reinforcer availability may elicit greater amounts of dopamine due to the drug-induced increase in the amplitude of phasic dopamine signals, similar to cocaine-induced increases in electrically stimulated release (Wu et al. 2001; Figs. 2a, b). Notably, exposure to cocaine and amphetamine also affects the processing of cues that are not related to drug intake (e.g., Puglisi-Allegra et al. 1994; Castellano et al. 1996; Cestari and Castellano 1996; Packard and White 1991). Additionally, the number of

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spontaneous phasic dopamine release events is increased dramatically due to the pharmacological effect of the drug which possibly leads to an association of an increased number of environmental stimuli with the drug experience (see Sect. 3.4). Together, this may explain how contextual cues not directly predicting drug administration become powerfully associated with the drug experience. In comparison to natural reinforcers and contextual cues, drug-associated cues are even more robustly “consolidated” due to the high contiguity and contingency of drug administration and these cues (i.e., the drug-induced facilitation of dopamine signaling is strongest immediately after intake and drug cues are never experienced separately from drug administration) (Fig. 2b). Consistent with this idea, learning associations between cues and natural reinforcers transiently affects the synaptic properties of dopamine neurons, while drug experience promotes long-lasting changes to the intrinsic and synaptic properties of dopamine neurons (Chen et al. 2008; Stuber et al. 2008). Such facilitation in Pavlovian learning may then promote the development of abnormal levels of dopamine release by drug-conditioned stimuli upon re-exposure (Redish 2004; Di Chiara and Bassareo 2007). With repeated training on a Pavlovian learning task using a natural reinforcer, the phasic dopamine signal shifts from reward delivery to the cue that predicts it (Day et al. 2007; Schultz et al. 1997). In contrast, dopamine signals in response to drug delivery in a drug self-administration task may not attenuate or may attenuate slower than with natural reinforcement because drugs directly activate the dopamine system. Therefore, this teaching signal may be constantly exhibited to both drug cues and the drug delivery itself. Thus, the brain continues to perceive drug delivery as a novel reward or positive prediction error despite repeated use (Redish 2004). Additionally, drug reward may be experienced as a reward of exaggerated magnitude, and thus the positive prediction error may be extraordinarily large (Tobler et al. 2005). Together, this may lead to aberrant reinforcement learning and eventual fixation on pursuit of drugs and compulsive intake. If dopamine acts to promote the repetition of actions that immediately precede rewarding events (Redgrave and Gurney 2006), drug exposure would immensely facilitate operant behavior that leads to drug administration. Alternatively, such drug-enhanced phasic dopamine signaling could also lead to the sensitized attribution of incentive salience to drug-related cues (Robinson and Berridge 1993). Thus, enhanced phasic signaling may promote abnormal responding to drug cues, whether due to aberrant learning and memory or motivation. Enhanced tonic dopamine concentrations may produce more exploratory activity and thus greater exposure of the organism to the drug environment including drug-related cues possibly promoting continued drug intake. This role for tonic dopamine fits well with the proposition that dopamine may have a function in overcoming the motivational costs required for completing tasks (Salamone and Correa 2002; Phillips et al. 2007). Tonically elevated dopamine concentrations may therefore keep the motivational cost for pursuing drug rewards minimal. Together, we posit that the drug-induced enhancement of phasic dopamine signaling will increase phasic release in response to previously weak or neutral


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stimuli and specifically strengthen associations of drug cues and drug delivery, whereas increased tonic dopamine levels may maintain the organisms motivation to continue drug intake by promoting seeking of cues/environments associated with the drug (Fig. 2b).

7.3

Long-Term Effects of Drug Exposure During Drug Withdrawal (Fig. 2c)

Withdrawal after chronic drug exposure has variable effects on tonic NAcc dopamine levels (see Sect. 4.1). Some studies report decreased dopamine concentrations while others have found no change or even increased basal levels. Lowered tonic dopamine levels during drug withdrawal may be associated with a reduced motivational state, leading to an enhanced susceptibility to drug seeking elicited by drug cues. Drug seeking could result in further exposure to drug cues, and thus eventually lead to elevated tonic levels of dopamine, as noncontingent presentation of drug-associated cues are known to cause elevations in tonic dopamine levels (see Sect. 5.1; Fig 2c). Increases in tonic dopamine could then, in turn, facilitate seeking behavior. Although little is known about the effect of drug withdrawal on the frequency or size of phasic dopamine release, we assume based on the findings discussed above that phasic signals to drug cues will be greater compared to (nondrug) cues associated with natural reinforcers (Fig. 2c), due to the abnormally strong association between drug and drug-predicting cues that develops during drug exposure (see Sect. 7.2; Fig. 2b). One explanation for enhanced phasic dopamine release to drug cues is that drugs of abuse produce an exaggerated reward magnitude, which is known to be reflected in dopamine signaling (Tobler et al. 2005). Another possibility is that the dopamine signal to drug cues escalates over time due to incubation of drug craving during abstinence (Grimm et al. 2001). In support of this proposition, it has been demonstrated that the activation of NAcc neurons by drug-associated cues is potentiated after 1 month of abstinence from cocaine self-administration (Hollander and Carelli 2007). Because phasic dopamine release is associated with the initiation of goal-directed behaviors (Roitman et al. 2004; Phillips et al. 2003; Stuber et al. 2005a, b; see Sects. 3.4.2 and 4.2), it follows that promotion of drug seeking in response to drug-related stimuli is more likely than seeking of natural rewards in response to associated nondrug cues. This assumption is consistent with the DSM-IV criterion that human drug addiction normally constitutes a progressive “narrowing” of the behavioral repertoire to that controlled by drug reinforcement rather than that guided by natural reinforcers, such as food or sex. Taken together, we propose that independent of tonic NAcc dopamine concentrations during withdrawal exposure to drug-associated stimuli activates phasic dopamine release more than nondrug related stimuli, and thus leads to fixation on drug-related behavior and eventually relapse to drug taking.

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8 Summary In this chapter, we review the current state of knowledge on how abused drugs, drug-associated cues, drug seeking, and drug withdrawal affect phasic and tonic dopamine signaling in the NAcc in animal models of addiction. For the sake of simplicity, we have neglected to address the core and shell subdivisions of the NAcc (e.g., Zahm and Heimer 1990) and referred to the NAcc as a whole. The vast majority of the reviewed studies sampled dopamine concentrations in the NAcc core. However, greater increases in phasic and tonic dopamine concentrations in the NAcc shell compared to the core have been identified in response to psychostimulants, morphine and ethanol (e.g., Pontieri et al. 1995; Ito et al. 2000; Lecca et al. 2007; Aragona et al. 2008; Howard et al. 2008). Furthermore, it has been shown that dopamine in the shell increases following self-administration of cocaine, but not following presentation of CS associated with the drug, whereas such CS predicting cocaine caused dopamine release in the core (Ito et al. 2000). These data suggest that the NAcc shell may be mainly implicated in the primary reinforcing effects of psychostimulants, whereas the core is preferentially involved in conditioned drug responses. The reviewed results are integrated with current ideas on the role of dopamine in addiction with an emphasis on a model illustrating phasic and tonic NAcc dopamine signaling during different stages of drug addiction. Each theory of dopamine function briefly outlined in this chapter has merits and it is not our intention to verify or falsify any of them, but rather to combine their different perspectives. The purpose of this chapter is not to provide a new psychology of addiction, but rather to give an updated perspective on potential neurochemical mechanisms underlying addiction. We have only focused on dopamine signaling here, although many other neurochemical systems have been identified as important contributors to addiction. Our model predicts that phasic dopamine release in response to drug-related stimuli will be enhanced over stimuli associated with natural reinforcers, which may result in aberrant goal-directed behaviors contributing to drug addiction.

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Amygdala Mechanisms of Pavlovian Psychostimulant Conditioning and Relapse Deanne M. Buffalari and Ronald E. See

Contents 1 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Amygdala Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 2.1 Intrinsic Circuitry of the Amygdala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 2.2 Afferent/Efferent Amygdala Projections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 3 Behavioral Models of Drug Abuse and Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 3.1 Conditioned Place Preference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 3.2 Self-Administration and Reinstatement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 3.3 Summary of Behavioral Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 4 Amygdala Neuronal Activity and Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 4.1 Immediate Early Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 4.2 Electrophysiological Recordings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 5 Downstream Signaling Cascades and Neuroadaptations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 5.1 Cellular and Molecular Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 5.2 Amygdala Neuroadaptations and Plasticity in Learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 6.1 Summary and Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 6.2 Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 6.3 Clinical Relevance and Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Abstract Psychostimulant addiction often consists of periods of sustained drug abstinence disrupted by periods of relapse and renewed heavy drug use. Prevention of relapse remains the greatest challenge to the successful treatment of drug addiction. Drug-associated cues are a primary trigger for relapse, as they can elicit intense craving for the drug. These cues become associated with the drug reward through Pavlovian learning processes that develop over multiple drug–cue pairings. The amygdala (AMY) is critical for such drug-related learning. Intrinsic and D.M. Buffalari (*) and R.E. See Department of Neuroscience, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA e-mail: [email protected]


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extrinsic circuitry position the AMY to integrate cue and drug-related information and influence drug-seeking and drug-taking behaviors. Animal models of conditioned drug reward, drug use, and relapse have confirmed the necessary role of the AMY for drug conditioned cues to control motivated behavior. Neurons within the AMY are responsive to the primary effects of psychostimulants, and more critically, they also respond to the presentation of drug-associated cues. The mechanisms by which conditioned cues come to influence drug-seeking behavior likely involve long-term plasticity and neuroadaptations within the AMY. A greater understanding of the associative learning mechanisms that depend upon the AMY and related limbic and cortical structures, and the process by which drug cues come to gain control over behavior that maintains the addictive state, will facilitate the development of more effective addiction treatments. Keywords Amygdala Psychostimulant Pavlovian Conditioning Relapse

Abbreviations AMY CPP DA NAcc SA VTA

Amygdala Conditioned place preference Dopamine Nucleus accumbens Self administration Ventral tegmental area

1 Introduction The rewarding properties of abused drugs, especially psychostimulants, drive both the initiation and continuation of drug use during the process of addiction (Wise 1980). The reinforcing properties of abused drugs (e.g., cocaine) are readily associated with environmental stimuli, such as the environment or context in which drugs are consumed, or discrete stimuli (e.g., drug paraphernalia). Through multiple pairings, these cues acquire conditioned reinforcing properties via associative learning. This process has particular relevance to the study of addiction, as often these cues elicit intense craving for the drug (Foltin and Haney 2000), and consequently serve to trigger relapse to drug taking in abstinent users (Kirby et al. 1995). Since prevention of relapse remains the greatest challenge to the successful treatment of drug addiction, a greater understanding of the associative learning processes that maintain the addictive state would facilitate the development of more effective addiction treatments.

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Multiple brain regions have been investigated for the role that they play in associative learning. The amygdala (AMY) has been an area of intense focus, due to the extensive afferent/efferent connectivity of the AMY with several brain regions that are relevant to associative conditioning of information that regulates affective states. In particular, the AMY has been thoroughly examined for the role it plays in fear conditioning (for review, see Maren 2005; Sigurdsson et al. 2007; Sah et al. 2008). Experimental paradigms have been developed and applied to investigate the independent phases of fear conditioning (acquisition, consolidation, and reconsolidation) (Debiec and LeDoux 2004), examine different nuclei of the AMY (Wilensky et al. 2006), and investigate the role of downstream signaling and neural adaptations (Schafe et al. 2001) in order to gather a more complete picture of how the AMY mediates such behaviors. In contrast to fear conditioning, the role of the AMY in appetitive conditioning has been far less studied. This is due, in part, to the large number of appetitive learning tasks that are unaffected by AMY lesions (Baxter and Murray 2002). Despite these findings, research dating back many years (Weiskrantz 1956) has clearly demonstrated that the AMY significantly contributes to appetitive learning. Tasks such as reinforcer devaluation (Hatfield et al. 1996; Malkova et al. 1997), second-order conditioning (Hatfield et al. 1996), Pavlovian approach behaviors (Hitchcott et al. 1997), conditioned suppression (Lee et al. 2005), and conditioned orienting (Groshek et al. 2005) are all sensitive to AMY lesions or direct pharmacological manipulations within the AMY. Given this abundant evidence with appetitive reinforcers, it comes as no surprise that the role of the AMY in appetitive learning related to drugs of abuse holds considerable interest for those in the field of addiction. Formulating a comprehensive view on the role of the AMY in the Pavlovian processes involved in addictive behavior poses a difficult challenge. Variations in the behavioral procedures (e.g., different stimuli, contexts, drug doses, species) can lead to large differences in the measured behaviors. Also, experimenters use different nomenclatures and target different nuclei or subnuclei of the AMY across different species. Finally, the associative processes of interest generally develop over multiple experiences of drug-stimuli pairings. Therefore, it can be difficult to pinpoint the relevant critical period for these AMY-mediated associations. In spite of the limitations, recent studies on the role of the AMY in addiction have employed more sophisticated behavioral models and have been more specific in targeting selective components of AMY anatomy and molecular targets. More advanced techniques in areas such as immunolabeling, electrophysiological recordings, measurements of downstream signaling, behavioral tasks, and functional in vivo imaging have greatly advanced our understanding of the role of the AMY in addiction in a relatively short time frame. This review will first discuss the anatomical complexity of intra-AMY circuitry and afferent/efferent projections. We will then examine two current animal models of addiction used to evaluate AMY mediation of drug taking and drug seeking. Subsequent sections will evaluate findings on specific aspects of AMY function in neurochemistry and neuropharmacology, measurements of neuronal activity, and downstream intracellular signaling

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processes. Finally, these data will be integrated in an attempt to provide a global understanding of the role of the AMY in the mediation of the learned associations that drive addiction.

2 Amygdala Anatomy Over the last two decades, anatomical and neurophysiological studies of the role of the AMY in Pavlovian conditioning with drug reward have revealed a marked degree of anatomical complexity and specialization. The AMY is an assembly of several major nuclei, each of which can be further divided into separate subnuclei, which also have their own subdivisions. These regions are unique in terms of cell type and morphology, electrophysiological characteristics, connectivity, and neurotransmitter content (Pitkanen et al. 1997; Sah et al. 2003). While the role of individual AMY subregions in drug addiction and relapse has been delineated to some extent, the exact function of some subregions remains to be fully clarified.

2.1

Intrinsic Circuitry of the Amygdala

For the purposes of the current review, we have utilized the nomenclature summarized by Pitkanen and colleagues (1997). As studies of AMY function and addiction have focused primarily on basolateral (lateral, basolateral, and accessory basal nuclei) and central regions, the current review will discuss these AMY nuclei proper, and not address studies on the extended AMY (specifically, the bed nucleus of the stria terminalis) or other AMY regions. For a review of the role of the extended AMY and drug addiction, the reader is referred to the excellent review by Koob (2003). The four main nuclei of the AMY can be further divided, with the lateral nucleus containing dorsolateral, ventrolateral, and medial subdivisions; the central nucleus containing lateral, capsular, intermediate, and medial subdivisions; the accessory basal containing magnocellular and parvocellular subdivisions; and the basal nucleus containing magnocellular, parvicellular, and intermediate divisions. Each subdivision has varying degrees of intraconnectivity and interconnectivity with the other subdivisions. Furthermore, each nucleus has varying degrees of interconnectivity with associated regions outside of the AMY. The lateral nucleus of the AMY does not display a high degree of intradivisional connectivity, but studies have shown both feedforward and feedback inhibition (Samson and Pare 2006). The dorsolateral division sends input to both the ventrolateral and medial divisions, but receives little reciprocal input. Furthermore, little connectivity exists between the ventrolateral and medial subdivisions (Pitkanen et al. 1995). Thus, input arriving in the lateral nucleus is generally processed in a lateral–medial/ventral manner, and then proceeds to other nuclei.


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In contrast, all of the subdivisions of the basal nucleus have a high degree of intradivisional connectivity. Furthermore, the parvocellular and magnocellular divisions are interconnected, and while the intermediate subdivision receives input from the parvocellular subdivision, it does not provide projections of its own or receive many inputs from the magnocellular subdivision (Savander et al. 1995). These anatomical characteristics allow for a great degree of information processing within the basal nucleus before synaptic relays to other regions. The accessory basal nucleus subdivisions have high intraconnectivity, but few connections with one another, making it more similar to the lateral nucleus (Savander et al. 1996). The subdivisions of the central nucleus have great intradivisional and interdivisional connectivity, with the exception, to some degree, of the intermediate subdivision. The capsular and medial subdivisions are interconnected, and the lateral subdivision sends projections to both, but receives little input in return. The intermediate subdivision is somewhat isolated, with meager projections from the capsular and lateral divisions, but sending little in terms of reciprocal projections (Jolkkonen and Pitkanen 1998). Of critical importance to intra-AMY processing are the connections between nuclei, which are extensive. The lateral nucleus sends projections to all the other nuclei, although the direct efferents to the central nucleus are sparse (Pitkanen et al. 1995; Stefanacci et al. 1992). The basal nucleus projects back to the lateral nucleus and sends heavier projections onto the central nucleus (Savander et al. 1997). In fact, single neurons within the lateral and basal nuclei of the AMY innervate multiple extranuclear AMY targets (Pitkanen et al. 2003), further evidence of the highly distributed processing typical of this structure. The accessory basal nucleus has efferents to the central nucleus and back to the lateral nucleus as well (Savander et al. 1997). The central nucleus receives convergent input from lateral, basal, and accessory areas, but sends meager projections in return. Hence, it is typically designated as the output nucleus. Often overlooked when considering AMY intrinsic connectivity are the intercalated cell masses. These small groups of GABAergic neurons lie mostly between the lateral/basal/accessory basal nuclei and the more medial central nuclei (Pare and Smith 1993a) and provide an important GABAergic projection to the central AMY (Pare and Smith 1993b). The intercalated cell masses have been shown to gate information between the more lateral nuclei and the central nucleus (Royer et al. 1999), perhaps creating a scenario whereby activation of lateral regions, via activation of intercalated cells, may actually inhibit the central nucleus (Rosenkranz et al. 2006). The lack of conclusive evidence as to the influence of “input” nuclei (lateral, basal, accessory basal) over the emergent output nucleus (central) makes interpretation of the results of initiation of activity in any of these regions difficult to predict. These intra- and interdivisional connections confer upon the AMY a great capacity for the generation and processing of several representations of sensory stimuli, even within individual nuclei. While the AMY has sometimes been conceptualized as a simple lateral to medial throughput, the anatomical and physiological evidence shows otherwise. These rich interconnections subserve Pavlovian

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conditioning in drug addiction by allowing the sensory representations of drug cues to become closely associated with the rewarding consequences of the drug. Further, these representations could be updated during the process of extinction, whereby memory information about the cues is accessed (cue = drug) and compared to the current sensory input (cue = no drug) to allow for flexibility in behavioral output as contingencies are changed. Of particular interest for ongoing research is the clarification of how the representations of these sensory cues can maintain drug desire and drug seeking even after periods of abstinence and/or extinction.

2.2

Afferent/Efferent Amygdala Projections

The AMY displays a high degree of regionally specific interconnectivity with several other brain regions that have been well implicated in drug addiction (Fig. 1). The long-held view of the AMY is that lateral/basal nuclei of the AMY serve as the input target for the sensory (e.g., thalamus) and midbrain (e.g., locus coeruleus) projections, with subsequent projections modulating central nucleus activity, which ultimately regulates behavioral output via downstream brainstem projections. However, it is unlikely that information processing simply occurs in a serial input–output manner, as sensory and thalamic regions display strong direct projections to central nuclei in addition to their lateral/basal projections (LeDoux

SENSORY CORTEX THALAMUS

DA/NE CELLS

“DISCRETE CUES”

“VALENCE INFO”

LAT

CEA ICMs

INTERACTION W/NAcc & PFC tomediate drugseeking behavior

BAS

AB

DOWNSTREAM PROJECTIONS CPP/reinstatement expression Autonomic activation

Fig. 1 Neural circuitry of cue-drug associations in the amygdala. Discrete cues activate the amygdala via sensory projections and become associated with drug reward via catecholaminegic inputs. After extensive intra-amygdala processing, downstream projections mediate drug-seeking behavior and sympathetic activation. LAT lateral nucleus, BAS basal nucleus, AB accessory basal, ICMs intercalated cell masses, CEA central nucleus, DA dopamine, NE norepinephrine, NAcc nucleus accumbens, PFC prefrontal cortex


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et al. 1985; Turner and Herkenham 1991; Linke et al. 2000). In fact, thalamic inputs onto neurons of the medial subdivison of the central nucleus of the AMY display activity dependent plasticity in a manner similar to the synapses in the lateral AMY heavily implicated in fear conditioning (Samson and Pare 2006). Further, a great deal of evidence has shown a dissociation of the roles of basolateral and central nuclei across many types of appetitive conditioning (Hatfield et al. 1996; Everitt and Robbins 2000; Parkinson et al. 2000). These data support the evidence derived from AMY anatomy (see above) suggesting the likelihood that the AMY contains several representations of stimulus-value associations, and that both serial and parallel processing are involved in the learning and expression of appetitive behaviors, such as those seen in addiction. From repeated drug use emerges complex behaviors including periods of heavy use, abstinence, and relapse, which often occur in repetitive cycles. Therefore, stimulus-value representations are constantly changing and updated based on drug use and motivational state. Extensive processing likely occurs within the AMY, with an integration of afferent input from many regions necessary to produce behavior most appropriate to the current conditions via efferent projections. While the AMY receives a great deal of sensory input, little of this originates directly from primary sensory regions. Rather, sensory association cortices send heavy projections to the lateral, basal, and central nuclei (McDonald 1998). Thalamic efferents also carry sensory information to all of the AMY nuclei (van Vulpen and Verwer 1989; Doron and LeDoux 2000). Furthermore, higher association cortices project to AMY nuclei, with the projections from the prelimbic cortex targeting mainly the lateral and central nuclei, and the infralimbic cortex projecting more prominently to central and basal nuclei (McDonald et al. 1996). The hippocampus projects most strongly to the lateral and basolateral nucleus with few projections to the central nucleus (Kishi et al. 2006), and the entorhinal cortex sends diffuse efferents to all AMY nuclei (McDonald and Mascagni 1997). It is important to note the extensive overlap in these disparate projections. For example, the AMY receives prominent projections from the ventral tegmental area (VTA) (Asan 1998, Brinley-Reed and McDonald 1999), as well as the locus coeruleus (Asan 1998), and nucleus of the solitary tract (Fallon et al. 1978). The overlap of sensory and higher association cortical projections with catecholaminergic input from midbrain sources allows the AMY to integrate information involving current sensory inputs, the valence of those stimuli, and past experiences. Similar to afferent systems, efferent projections of the AMY are comparably diverse. The lateral and basolateral nuclei send outputs to prefrontal regions (McDonald 1991; Gabbott et al. 2006). The most prominent projection to the hippocampus arises from the basal nucleus (Pikkarainen et al. 1999). Other projections arise from basolateral regions to the nucleus accumbens (NAcc) (Shinonaga et al. 1994). The basolateral AMY also projects to the central AMY and beyond to the bed nucleus of the stria terminalis (Dong et al. 2001). All of these regions play prominent roles in the development and expression of addictive behaviors. The projections of the central nucleus are quite different from the lateral and basal nuclei, targeting various subcortical regions including the hypothalamus

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(Gray et al. 1989), the bed nucleus of the stria terminalis (Sun et al. 1991), and the noradrenergic neurons of the locus coeruleus (Van Bockstaele et al. 2001). These efferent connections may mediate behavioral responding to drug cues and autonomic nervous system activation to drugs of abuse. In summary, the extremely complex intrinsic and extrinsic connectivity of the AMY likely subserves several functions relevant to drug addiction. First, association of sensory input with dopaminergic (DA) and possibly noradrenergic signaling appears to contribute to the formation of associations between discrete or contextual cues with the drug-induced state. Furthermore, as it is unlikely that such memories are simply stored in the AMY, projections to the hippocampus and cortex may mediate transfer to other regions for long-term memory storage. Interconnectivity of the AMY with these regions enables integration of previously formed associations with new information (as may occur during extinction of responding for drugs of abuse). Based on the well-established role of glutamatergic projections from the prefrontal cortex to ventral and dorsal striatal regions in the reinstatement of drug seeking (McFarland and Kalivas 2001; Kalivas and McFarland 2003; McFarland et al. 2004) and subjective craving in human drug addicts (Volkow et al. 2006), the AMY probably modulates transmission in this pathway through extensive efferent projections to both regions. In fact, neurons within the NAcc receive converging input from the prefrontal cortex and AMY at the level of a single neuron (O’Donnell and Grace 1995), supporting the likelihood that these regions can modulate one another, as well as the NAcc. Further, many neurons from the AMY that project to the prefrontal cortex have collateral projections to the NAcc (Shinonaga et al. 1994). Medial prefrontal cortical neurons respond to Pavlovian conditioned stimuli, and these responses depend on AMY input (Schoenbaum et al. 2003). In fact, prefrontal neurons that receive excitatory input from the AMY are also activated by aversively conditioned cues (Laviolette et al. 2005). AMY inputs also preferentially modulate prefrontal cortical neurons that project to the NAcc (McGinty and Grace 2008). Therefore, the AMY is well positioned to modulate the output of this prefrontal–accumbens pathway that mediates drug seeking.

3 Behavioral Models of Drug Abuse and Relapse Clinical investigations, particularly when combined with modern imaging techniques, have provided unique insight into the brain structures involved in addiction. However, few of these studies are able to examine addictive behaviors at the points of initiation and progression, only their late stage resultant effects. Furthermore, these studies seldom examine patients in a drug-induced state. Increasingly sophisticated animal models of addiction have expanded our understanding of the development of motivated behaviors for drugs of abuse. The two models of greatest relevance to a discussion of the Pavlovian processes contributing to the


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Fig. 2 Phases of conditioned place preference

development of addiction are the conditioned place preference (CPP) paradigm and the drug self-administration (SA) and relapse model.

3.1

Conditioned Place Preference

The CPP model involves three phrases: habituation, conditioning, and testing (with some studies including extinction and reinstatement test phases, Fig. 2). The paradigm evaluates whether the pairing of one specific context with a drug produces a preference for that context (for review see Bardo and Bevins 2000; Tzschentke 2007). In the habituation phase, animals are acclimated to two distinct environments. Then, during training, one context is consistently paired with the subjective experience of the drug, hence the Pavlovian aspect of this task. Animals are then tested in a drug-free state for their display of a conditioned preference for one context versus the other. Preference is measured as a significant difference in the number of entries or time spent in the drug-paired context as compared to the vehicle-paired context. This behavior can then be extinguished with repeated drugfree tests or confinement of the rat to the drug-paired context without a pre-session drug injection. Subsequent testing can determine if exposure of the animal to different stimuli (e.g., drug priming injections) will reinstate the extinguished CPP. Both cocaine and amphetamine support CPP. Lesions of the lateral, central, and basolateral AMY nuclei before conditioning disrupt the acquisition of cocaine-CPP (Brown and Fibiger 1993). More specific investigations demonstrated that lesions of the lateral nuclei, but not basal or central, also attenuated both the acquisition and expression of amphetamine-CPP (Hiroi and White 1991). Recent studies confirmed

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that lesions of the basolateral AMY complex performed prior to cocaine-CPP training disrupted acquisition, with similar lesions given after conditioning disrupting cocaine-CPP extinction (Fuchs et al. 2002). Basolateral AMY inactivation with sodium-channel blockade immediately after amphetamine conditioning sessions also disrupted CPP acquisition, suggesting that the AMY may play a role in the consolidation of CPP (Hsu et al. 2002). However, although the central AMY seems to mediate expression, but not acquisition of this behavior, injections of amphetamine directly into the central AMY, but not the basolateral, supported CPP, which complicates interpretation of these results (O’Dell et al. 1999). In addition to studies that have disrupted AMY-based CPP, others have demonstrated a facilitation of CPP extinction, but not acquisition. Intrabasolateral AMY injections of the NMDA partial agonist, D-cycloserine, cause a facilitation of CPP extinction, but not acquisition (Botreau et al. 2006). Similarly, injections of glucose directly into the basolateral AMY (mainly targeting the basal nucleus) also enhanced extinction training of amphetamine-CPP (Schroeder and Packard 2003), as did the muscarinic agonist, oxotremorine (Schroeder and Packard 2004). In summary, while the role of the basolateral AMY in acquisition, expression, consolidation and extinction of this behavior has been established, the central nucleus does not seem to be required for this aspect of drug conditioned reward behavior (but see O’Dell et al. 1999).

3.2

Self-Administration and Reinstatement

While CPP has provided a useful model for studying the role of the AMY in conditioned drug reward, the procedure is inherently limited due to the lack of contingent drug administration. A more widely accepted animal model of addiction with greater face validity is the drug SA and relapse paradigm (Epstein et al. 2006). Pavlovian conditioning to drug cues and contexts plays an important role in this paradigm as well.

Fig. 3 Phases of administration and relapse paradigm


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Four main experimental phases can be assessed using the SA/relapse paradigm: acquisition, maintenance, extinction/abstinence, and reinstatement (Fig. 3). Following implantation of jugular catheters, animals learn to self-administer an intravenous (IV) drug using operant conditioning whereby a set number of operant responses (usually on a lever) results in an IV drug infusion. Each infusion may also be paired with discrete cues (e.g., lights and/or tones). Thus, throughout training, both the SA chamber and the cues presented with the infusion become associated with drug delivery and the rewarding effects of the drug. Acquisition transitions to the maintenance phase once the animal displays stable responding for the drug. Upon reaching a set SA criterion (minimum number of infusions over a set number of days), animals move from active drug SA into the extinction phase of the paradigm. During extinction, the subject is placed in the same test environment and provided access to response levers, but no drug infusions or conditioned stimulus presentations occur in response to lever responding. Therefore, animals gradually reduce responding on the previously drug-paired lever over consecutive sessions. Once an extinction criterion has been reached, subjects undergo trials of reinstatement testing. Reinstatement testing evaluates the ability of different factors to induce reinstatement of responding on the previously drug-paired lever. These tests directly model exposure of abstinent drug users to specific factors known to trigger relapse, such as drug paraphernalia, small amounts of the drug, or stress. Similar to humans, exposing animal subjects to a priming injection of the drug (drug-primed reinstatement), exposure to discrete cues (conditioned-cue reinstatement), or administration of some form of stressor (stress-induced reinstatement) will reliably reinstate drugseeking behavior (Shaham et al. 2003). Excitotoxic lesions of the basolateral AMY have no effect on cocaine SA in rats; however, these same lesions (Meil and See 1997) or reversible inactivations (Grimm and See 2000; McLaughlin and See 2003) abolish the ability of cocainepaired cues to reinstate cocaine seeking. Similar AMY lesions also attenuate the ability of a second-order cue previously associated with cocaine to support responding (Whitelaw et al. 1996; Kantak et al. 2002). Attempts to examine neurotransmitter specificity have shown that DA D1, but not D2, receptor antagonists administered directly into basolateral AMY block expression of conditioned-cue reinstatement (See et al. 2001), while muscarinic receptor antagonism blocks acquisition, but not expression of reinstatement (See et al. 2003). However, neither of these antagonists affect the re-establishment of cocaine SA. In order to more specifically examine the role that conditioned cues play in the learned associations that underlie reinstatement of cocaine seeking, our laboratory developed a Pavlovian training approach to discretely associate cocaine infusions and cues in cocaine-experienced animals (Kruzich et al. 2001). Amidst several days of active cocaine SA in the absence of discrete cues, animals experience a single learning session during which passive cocaine infusions are discretely paired with the presentation of a novel light-tone stimulus complex. Following extinction training, these cues trigger cue-induced reinstatement. This paradigm allows for the study of the acquisition and consolidation of cue–cocaine associations distinct from the expression of the learned behavior guided by conditioned cues.

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inactivations of the basolateral AMY immediately prior to the conditioning session or before reinstatement testing both disrupt conditioned-cue reinstatement, while inactivation of the central AMY disrupts expression, but not acquisition (Kruzich and See 2001). Blockade of D1 receptors in the basolateral AMY during acquisition also disrupts subsequent cue-induced reinstatement (Berglind et al. 2006). Inactivation (Fuchs et al. 2006) or NMDA receptor blockade (Feltenstein and See 2007) immediately after conditioning sessions (consolidation) disrupt cue-induced drug seeking as well. These results confirm and extend previous studies for the AMYmediated development of drug–cue associations.

3.3

Summary of Behavioral Findings

Integrating the multiple studies that have examined the role of the AMY and its neurotransmitter regulation in psychostimulant CPP and SA supports the conclusion that the AMY is indeed critical for motivated drug reward and drug seeking. Furthermore, establishment of drug–cue associations relies on a convergence of AMY inputs that include DA, glutamate, and acetylcholine. The AMY is involved at key phases in the development of these behaviors. The lateral nucleus of the AMY is essential for acquisition, expression, and extinction of cocaine-CPP. Reinstatement caused by conditioned cues is attenuated by basolateral AMY lesions, pharmacological inactivation during acquisition or consolidation, or immediately prior to reinstatement. However, it appears that the central AMY is involved in the expression of these reinstatement behaviors only. These behavioral models and resultant findings have provided the basis for the development of further studies examining measurements of neuronal activation during each phase of behavior, downstream signaling, and cellular and molecular events related to these processes, and neuroadaptations that may be critical for susceptibility to relapse.

4 Amygdala Neuronal Activity and Addiction While studies utilizing behavioral paradigms of drug reward and drug seeking have clearly implicated the AMY in addiction, other experimental approaches have been applied to directly discern neuronal activity in the AMY relevant to drugs of abuse. The two primary techniques that have been most commonly utilized are immunolabeling of immediate early genes and gene products (e.g., c-fos) and direct recordings from AMY neurons. These techniques are combined with the identification of cell type (from recordings or staining) or projection target (from tract tracing) in an attempt to examine the types of neurons activated during behavioral tasks, and where those cells may project.


4.1

85

Immediate Early Gene Expression

Acute cocaine and amphetamine injections both lead to an increase in c-fos immunoreactivity in the lateral, basal, and central AMY (Brown et al. 1992; Engber et al. 1998; Mead et al. 1999). The context in which the drugs are administered also plays a critical role in neuronal activation. Amphetamine administration in the home cage has been shown to increase c-fos in the lateral, basal, and central nuclei, with a potentiated effect in the lateral and basal nuclei when administration occurs in a novel environment. Administration of amphetamine in a novel environment caused a decrease in activity of central AMY neurons (Day et al. 2001), suggesting that the activation of lateral/basal populations may be of importance for the association between drug and environment/contextual cues, which does not occur in central AMY regions. Presentation of a cocaine or amphetamine-paired environment also leads to increased c-fos expression in the lateral, basal, and central AMY (Brown et al. 1992; Mead et al. 1999). Cocaine-CPP testing caused increased c-fos immunolabeling of both projection neurons and local circuit interneurons in the AMY (Miller and Marshall 2004). These activated projection neurons send efferents to the NAcc, supporting the known interactions of AMY-PFC-NAcc in modulating these types of behaviors (Miller and Marshall 2005). Further, those neurons in the lateral and basal AMY nuclei that were activated during amphetamine-CPP testing displayed increased synaptophysin varicosities, indicative of synaptogenesis, as well as increased TrKB receptor immunoreactivity (Rademacher et al. 2006), lending support to the idea that the AMY is a critical site of drug–contextual cue association.

4.2

Electrophysiological Recordings

Neurophysiological data regarding the role of the AMY in models of addiction is fairly limited, as most studies have focused on NAcc and the VTA. However, evidence to date has demonstrated that cocaine has complex effects on AMY activity. Lateral and central AMY neurons display excitatory or inhibitory responses to IV cocaine administration (Ben-Ari and Kelly 1976; Callahan and Cunningham 1991). These studies did not differentiate between the types of neurons being recorded; however, their average firing rate indicates that the recorded population likely included many interneurons (Rosenkranz and Grace 1999). These results are not surprising, in that DA itself causes both excitatory and inhibitory responses in the AMY (Rosenkranz and Grace 1999), as do norepinephrine (Buffalari and Grace 2007) and serotonin (Rainnie 1999). The excitatory and inhibitory actions of cocaine may correlate with neuronal cell type. IV amphetamine causes mostly slow onset, long lasting inhibition in AMY neurons, with a small proportion of cells showing excitation (Bashore et al. 1978, but see Wepsic and Austin 1972).

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As IV cocaine administration causes DA efflux across many brain regions highly interconnected with the basolateral AMY, cocaine directly applied in the AMY would indicate whether these effects are due to direct actions vs. secondary effects via activity changes in afferent structures. Iontophoretic cocaine application in the AMY led to an inhibition of spontaneous activity in a large proportion of AMY neurons in the lateral, basolateral, and central nuclei (Cunningham et al. 1989), with no evidence of any neuronal excitation. For cocaine SA, IV drug delivery results in actions that are not restricted to the AMY. Therefore, the impact of cocaine is a complex mixture of excitatory and inhibitory responses in the lateral, basal, and central nuclei. Thus, a more complex relationship exists between basolateral and central AMY activity than the simple lateral to medial transmission pattern, whereby the former solely activates/inactivates the latter. Inhibition of lateral AMY neurons, which have glutamatergic projections to central AMY neurons, should cause a decrease in the firing of central AMY neurons. Alternatively, inhibition of lateral neurons could decrease excitation of intercalated cell masses neurons, and disinhibit central AMY neurons. This scenario is complicated by the actions of IV psychostimulants on AMY afferent regions. The most interesting and relevant studies of neuronal activity have involved neuronal recording in awake behaving rats actively engaged in established cocaine SA (Fig. 4) (Carelli et al. 2003). In these studies, several different types of neuronal responses have been characterized. Of interest, a subset of neurons displayed “postresponse excitations,” showing significant increases in activity just after behavioral responding. These same neurons were excited when cocaine-associated

Fig. 4 Extracellular recordings from neurons of the AMY in rats actively selfadministering cocaine (Carelli et al. 2003). Horizontal bar in top panel represents cocaine delivery (R: reinforced response), in bottom panel represents tonelight presentation (S: stimulus). Note the neuronal response to the tone-light in the absence of cocaine


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stimuli were presented in the absence of the cocaine reinforcer. Interestingly, NAcc neurons respond in a manner very similar to the AMY (Carelli 2002), perhaps partially due to basolateral AMY efferents to the NAcc. Clinical investigations of drug addiction have often combined reports of craving for the drug and general physiological indices (e.g., skin conductance responses, cortisol release, etc.) with in vivo measurements of brain activation. Craving states elicited by drug-associated cues or stressful situations in human drug addicts have been linked to activation of similar neural circuitries as reported in animal models of relapse to drug seeking. Exposure to cocaine-associated cues increases drug craving in abstinent users (Childress et al. 1993). The AMY has emerged as a structure with a prominent role in cue-induced craving in human addicts, similar to the role seen for reinstatement of drug seeking in animal models. The presentation of drug-associated cues or imagery results in activation of the AMY in abstinent cocaine users (Grant et al. 1996; Childress et al. 1999; Kilts 2001), although this AMY activation is not always apparent (Garavan et al. 2000). Studies of neuronal responses to psychostimulant cues advance our understanding of how such cues might support SA and trigger relapse. However, much work remains to be done in this area. The limited existing studies have only examined neuronal responses in naı¨ve animals or in animals reliably self-administering cocaine. Therefore, while these studies provide valuable data on the responding of AMY neurons to cocaine and cocaine-related cues, nothing is known about the development and progression of responding over the course of the addictive process. Of particular interest would be characterizing how the responses of AMY neurons, particularly those that respond to cocaine-associated cues, develop through various phases of cocaine SA and cocaine-seeking behaviors (acquisition, maintenance, and extinction). Furthermore, as the AMY plays such an important role in conditioned-cue induced reinstatement, linking the firing patterns of AMY neurons to cocaine conditioned cues during reinstatement of cocaine seeking would strengthen the argument that relapse is driven by basolateral AMY activity.

5 Downstream Signaling Cascades and Neuroadaptations The clinical profile of addiction as a chronic relapsing disorder strongly supports the role of permanent drug-induced neuroadaptations in glutamatergic and DAergic reward learning pathways. Such neuroadaptations can lead to impaired decisionmaking skills, hyperresponsivity to drug cues or contexts, and persistent habit-like behaviors that are insensitive to the negative consequences of drug abuse. The characterization of addiction as a maladaptive learning-related phenomenon has prompted examination of the effects of psychostimulants on cellular events and signaling cascades related to synaptic plasticity (Thomas et al. 2008). While the majority of studies on AMY neuroplasticity have focused on fear learning paradigms (Maren 2005; Sigurdsson et al. 2007; Sah et al. 2008), more recent

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investigations have also examined appetitive learning (Rademacher et al. 2006). Much of the work in the addiction field has centered on the NAcc and DAergic neurons of the VTA (Kauer and Malenka 2007; Thomas et al. 2008). However, based on evidence for the pivotal role of the AMY in drug–cue associative learning and cue-induced relapse, recent investigations have begun to assess the AMY as a potential site of synaptic plasticity that may account for the type of persisting changes that maintain chronic addiction (Goussakov et al. 2006; Rademacher et al. 2006). The role of DA in SA behavior has been well established, as D1 and D2 receptors play a critical role in the acquisition and reinstatement of drug seeking. DA receptors are primarily located postsynaptically on neurons of the lateral AMY (Pinto and Sesack 2008), where these associative events likely occur. DA in the basolateral AMY causes an overall decrease in the firing rate of projection neurons (Rosenkranz and Grace 1999). This reduced activity may seem counterintuitive to activation by psychostimulant SA. However, DA also preferentially facilitates input from sensory association areas (Rosenkranz and Grace 1999). This facilitation is mediated via an increase in the signal-to-noise ratio, and benefits the association of sensory information representing drug cues with reward-related information representative of the primary drug reinforcer.

5.1

Cellular and Molecular Mechanisms

D1 receptors are coupled via Gs proteins to protein kinase A activation (Missale et al. 1998). This activation has multiple potential downstream targets, including ERK and PI3-K. Acute cocaine leads to D1-dependent increases in phosphorylated ERK levels within the lateral and central AMY (Valjent et al. 2004), and inhibition of ERK prevents the acquisition of CPP (Valjent et al. 2000), a behavior dependent on AMY function. While inhibition of ERK does not affect cocaine SA, ERK plays a role in cue-induced reinstatement of psychostimulant-seeking behaviors (Lu et al. 2005). Exposure to cocaine cues after 1 day of withdrawal increased phosphorylated ERK in the basolateral but not central AMY, while the same treatment after 30 days of withdrawal caused the reverse effect. Furthermore, inhibition of ERK phosphorylation in the central AMY after 30 days decreased conditioned-cued responding, while basolateral AMY infusions had no effect. Finally, activation of ERK phosphorylation in the central AMY at 1 day of withdrawal enhanced responding for drug-associated cues (Lu et al. 2005). Akt (also known as protein kinase B) is another signaling molecule that is affected by psychostimulants. Levels of phosphorylated Akt are increased in the AMY after acute treatment with cocaine, but decreased after chronic treatment (Perrine et al. 2008). GSK-3 protein levels are also decreased after 14 days of noncontingent cocaine treatment, which is surprising given that Akt negatively


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regulates GSK-3 activity. ERK regulates further neuroadaptations that could play a significant role in addiction. For example, increased ERK proteins can cause activation of transcription factors such as CREB and Elk-1 (Valjent et al. 2001). In turn, these factors can regulate gene expression necessary for modifications at the level of the synapse. Immediate early genes such as c-fos, zif268, and JunB have also demonstrated responses to psychostimulants specific to the AMY (Radwanska et al. 2005). After extinction, re-exposure to cocaine cues upregulated zif268 in the lateral AMY regions (Thomas and Malenka 2003). Inhibition of zif268 in the basolateral AMY also blocked cue-induced reinstatement of cocaine seeking (Lee et al. 2005). These immediate early genes have also been implicated in learning and plasticity processes, further linking the convergence of the development of addiction with cellular modifications within the AMY (Nestler 2002).

5.2

Amygdala Neuroadaptations and Plasticity in Learning

While many of these effects are likely mediated via DAergic signaling at the D1 receptor, there are many other upstream regulators of ERK and other molecules. The phosphorylated ERK signal in the central AMY after 30 days of withdrawal is blocked by either NMDA receptor antagonists or mGLUR2/3 receptor agonists (Lu et al. 2005). As discussed earlier, glutamatergic afferents to the lateral AMY are likely essential to the association of cues with the rewarding properties of psychostimulants. These synapses constitute the critical site for long-term potentiation that occurs as a result of fear conditioning (Sigurdsson et al. 2007). Furthermore, BDNF can lead to activation of ERK. BDNF has been shown to have a role in various forms of neuroplasticity, including addiction (Thoenen 1995). The AMY contains BDNF-immunoreactive cells (Meredith et al. 2002), and withdrawal from cocaine SA increases BDNF protein in the AMY after 30 or 90 days (Grimm and See 2000). Several other effects of BDNF in brain regions relevant to addiction (e.g., NAcc, Graham et al. 2007 and prefrontal cortex, Hearing et al. 2008) have been investigated; however, studies have not yet been expanded to include consideration of the AMY. The relation of AMY-dependent fear learning to plasticity and AMY synapses has been well established and developed. In comparison, reward-related learning in the AMY has been far less investigated. An important first step would be to examine how acute or repeated psychostimulant administration affects plasticity at AMY synapses. This could be extended to examine plasticity (or occlusion of plasticity) in animals at various stages of CPP and SA behavior. Further investigations into the cellular and molecular mechanisms of these processes would expand our currently limited knowledge on the relation of appetitive drug-reward learning and plasticity in the AMY.

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6 Conclusions 6.1

Summary and Synthesis

The AMY clearly plays a critical role in the associative learning involved in the development of addiction. However, to understand the neurobiology of addiction, one must consider the AMY in the context of the larger limbic and cortical circuitry that underlies psychostimulant addiction. The importance of sensory cortical, thalamic, and hippocampal input that conveys information about environmental cues to the AMY has already been reviewed. DA and norepinephrine modulate information about drug reward in the AMY via projections from the VTA and LC/NTS as well. These multiple streams of information are integrated and expressed via neuronal responding at the cellular level in the AMY, likely through synaptic plasticity at inputs to lateral AMY neurons, in a manner similar to fear conditioning. The role of efferent projections from the AMY that mediate conditioned responding for psychostimulants are less clear. Prior research has implicated the prefrontal cortex and the NAcc in these processes, as well as the mesolimbic DA system originating in the VTA. The lateral/basolateral AMY projection to the NAcc is important for generating goal-directed behaviors (Setlow et al. 2002), including drug seeking (Di Ciano and Everitt 2004). Neuronal inactivation of both the basolateral AMY (Grimm and See 2000) and the NAcc core (Fuchs et al. 2004) disrupts conditioned-cue reinstatement of drug-seeking behavior. Furthermore, disruption of the interactions between these structures reduces cocaine seeking (Di Ciano and Everitt 2004). Cocaine cues also increase glutamate levels in the NAcc (Hotsenpiller and Wolf 2002), which could be due to increased AMY input. These data are congruent with human imaging studies showing that cocaineassociated cues activate both the NAcc (Kilts et al. 2001) and the AMY (Childress et al. 1999; Grant et al. 1996) in abstinent cocaine users. Increased striatal DA is associated with enhanced craving in abstinent users only when presented with cocaine-associated cues (Volkow et al. 2008), suggesting glutamatergic input from the AMY to the striatum may be critical for craving states. DA in the AMY is also important for cue-induced drug seeking (See et al. 2001). Neurons of the AMY and NAcc respond similarly to cocaine-paired cues (2002; Carelli et al. 2003), and basolateral AMY input to the accumbens is critical for reward-seeking behaviors (Ambroggi et al. 2008). Thus, projections from the AMY to the accumbens are clearly also critical for drug seeking. The prefrontal cortex is another region with a well established role in maintaining addictive behaviors. Cocaine-associated cues activate various areas of human prefrontal cortex (Childress et al. 1999; Kilts et al. 2001), and the magnitude of change in these regions correlates with self-reported craving levels (Breiter et al. 1997). Conditioned-cue induced reinstatement in rats is associated with c-fos increases in prefrontal cortex (Zavala et al. 2007) and cocaine seeking after prolonged abstinence is correlated with increased prefrontal c-fos, arc, and zif268


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gene expression (Hearing et al. 2008). Conditioned cues also increase glutamate levels in the prefrontal cortex (Hotsenpiller and Wolf 2002) and inactivation of the anterior cingulate or prelimbic cortex disrupts conditioned-cue induced cocaine seeking (McLaughlin and See 2003). The prefrontal cortex likely modulates AMY output as well as supports drug-seeking behavior via projections to NAcc.

6.2

Future Research

An area in need of further research is the cellular and molecular adaptations within the AMY that promote the transition from initiation of limited drug use to addiction. Long-term potentiation at synapses in the VTA is evident after a single cocaine (Ungless et al. 2001) or amphetamine (Faleiro et al. 2004) exposure. This plasticity is NMDA (Ungless et al. 2001) and D1 (Dong et al. 2001) receptor dependent, and is seen after repeated cocaine as well (Borgland et al. 2004). Other studies have suggested roles for ERK and PKA in the VTA in cocainedependent long-term potentiation (Thomas et al. 2008). These results are consistent with studies examining long-term potentiation and fear conditioning within the AMY. AMY plasticity is dependent on NMDA receptors, MAPK, ERK, CREB, and protein synthesis (for review see Schafe et al. 2001; Rodrigues et al. 2004). However, these two lines of study have not yet converged with an examination of whether AMY plasticity is important for drug–cue associations in addiction. Longterm plasticity and neuroadaptations could support how cues associated with psychostimulants come to exert powerful control over goal-directed behaviors, in particular drug seeking. Basolateral AMY neurons normally switch their firing during behavioral reversals to encode cue outcome rather than cue identity. After chronic cocaine administration, these neurons become inflexible, either firing in a nonspecific manner or maintaining prereversal firing patterns (Stalnaker et al. 2008). While this may partially explain decision-making deficits in addicts, it could also explain the ability of cues to precipitate drug seeking long after extinction or abstinence. Although positive reinforcement plays a major role in the development of addictive behaviors, abundant evidence suggests that tolerance to the rewarding properties of drugs causes secondary adaptations that promote increased drug use and dependence. That is, persistent drug use involves maladaptive neural activity and dysregulated homeostasis that, when the drug is withheld, results in aversive psychological and physiological effects (Kreek and Koob 1998). Such a scenario may promote drug use through negative reinforcement, whereby an individual continues use of the drug to avoid the negative consequences of drug withdrawal. Pavlovian conditioning via the AMY plays a vital role in how withdrawal symptoms precipitate drug-taking behavior. Studies have cited the involvement of medial portions of the central AMY in the negative affect associated with withdrawal stages (Koob 2008). Recent evidence also demonstrates that plasticity at

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synapses in the lateral and central AMY plays a role in the negative emotional states associated with cocaine withdrawal (Goussakov et al. 2006; Fu et al. 2007).

6.3

Clinical Relevance and Application

The role of the AMY in learning processes that contribute to psychostimulant addiction and relapse is now abundantly clear. What remains to be delineated is the role of different subnuclei, as well as how AMY neurons come to encode cocaine cues. Investigations into the neuroadaptations and synaptic plasticity that underlie these firing patterns will expand our knowledge of the precise role of the AMY in addiction. Treatment approaches must consider the powerful influence that drug cues have over abstinent drug users seeking treatment. While the strength of this conditioning can be detrimental to successful treatment, conditioning may also be used to the patients’ advantage. Exposure therapy and the formation of new associations can be applied in attempts to control relapse. While the highly context and cue-specific nature of the previously formed drug–cue associations make such treatments challenging, a better understanding of the neurophysiological and neurochemical underpinnings of AMY-based associative mechanisms contributing to addiction will facilitate the development of pharamacotherapies and behavioral treatments that will improve addiction treatment outcomes.

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Prefrontal Cortical Regulation of Drug Seeking in Animal Models of Drug Relapse Heather C. Lasseter, Xiaohu Xie, Donna R. Ramirez, and Rita A. Fuchs

Contents 1 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Environmental Stimulus-induced Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.1 Relapse Following Extinction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 2.2 Relapse Following Abstinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 3 Drug-primed Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 3.1 Anterior Cingulate and Prelimbic Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 3.2 Infralimbic Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 3.3 Orbitofrontal Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4 Stress-induced Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4.1 Anterior Cingulate and Prelimbic Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 4.2 Infralimbic Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 4.3 Orbitofrontal Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 5 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Abstract Prefrontal cortical dysfunction is thought to underlie maladaptive behaviors displayed by chronic drug users, most notably the high propensity for relapse that severely impedes successful treatment of drug addiction. In animal models of drug relapse, exposure to drug-associated stimuli, small amounts of drug, and acute stressors powerfully reinstate drug seeking by critically engaging the prefrontal cortex, with the anterior cingulate, prelimbic, infralimbic, and orbitofrontal subregions making distinct contributions to drug seeking. Hence, from an addiction treatment perspective, it is necessary to fully explicate the involvement of the prefrontal cortex in drug relapse. Keywords Anterior cingulate Drug seeking Extinction Infralimbic Orbitofrontal Prefrontal cortex Prelimbic Reinstatement H.C. Lasseter, X. Xie, D.R. Ramirez and R.A. Fuchs (*) Department of Psychology, University of North Carolina, Chapel Hill, NC 27599-3270, USA e-mail: [email protected]


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Abbreviations ACC AMPA BDNF BLA BM BNST CeA CS DH dlCPu GABA IL LTN NA NAcore NAshell NBm OFC p-ERK PL RGS4 TTX VH VP VTA

Anterior cingulate cortex Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Brain derived neurotrophic factor Basolateral amygdala Baclofen and muscimol Bed nucleus of the stria terminalis Central amygdaloid nucleus Conditioned stimulus Dorsal hippocampus Dorsolateral caudate-putamen Gamma-aminobutyric acid Infralimbic cortex Lateral tegmental nucleus Nucleus accumbens Core region of the nucleus accumbens Shell region of the nucleus accumbens Nucleus basalis of Mynert Orbitofrontal cortex Phospho-extracellular-related kinase Prelimbic cortex Regulator of G-protein signaling 4 Tetrodotoxin Ventral hippocampus Ventral pallidum Ventral tegmental area

1 Introduction Clinical studies suggest that structural, physiological, and functional abnormalities in the prefrontal cortex facilitate drug craving and drug seeking, which can be triggered by drug-associated environmental stimuli, small amounts of drug, or stress (Ehrman et al. 1992; Foltin and Haney 2000; Rohsenow et al. 2007). The transition from recreational drug use to drug addiction may be related to neural predisposition to drug addiction or neural plasticity resulting from prolonged drug exposure (Franklin et al. 2002; Volkow et al. 2002). Chronic drug users typically present with decreased gray matter density and reduced baseline blood glucose metabolism in the frontal cortex (London et al. 1999; Volkow and Fowler 2000; Franklin et al. 2002; Matochik et al. 2003). At the same time, frontal cortical

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regions of drug users exhibit heightened metabolic activity upon exposure to relapse triggers, which is positively correlated with the intensity of self-reported craving (Grant et al. 1996; Breiter et al. 1997; Childress et al. 1999; Garavan et al. 2000; Bonson et al. 2002; Sinha and Li 2007). In addition to the neural correlates of drug seeking identified in human studies, preclinical studies in rodents directly support the idea that prefrontal cortical subregions make distinct contributions to relapse behaviors (see Table 1), as will be described in this chapter. Based on its connectivity, the prefrontal cortex is ideally positioned to receive information about the salience and motivational significance of relapse triggers from limbic and sensory areas and, in turn, to exert executive control over the selection and initiation of drug-seeking behavior via its output to the motor system. The rodent prefrontal cortex is an aggregate of several cortical regions, including the anterior cingulate (ACC), prelimbic (PL), infralimbic (IL), and orbitofrontal cortices (OFC). These prefrontal cortical subregions all receive input from the mediodorsal thalamus (Uylings and van Eden 1990), but make distinct contributions to drug seeking likely based on their differential connectivity with other elements of the cue-induced, drug-induced, and stress-induced relapse circuitries summarized in Fig. 1 (for detailed reviews, see Shaham et al. 2003; Schmidt et al. 2005b; Feltenstein and See 2008). Importantly, future studies will need to verify the existence of functionally significant interconnections between the circuitry components depicted in the figure.

2 Environmental Stimulus-induced Relapse Several animal models of cue-induced drug relapse have been developed to assess the neural correlates of incentive motivation for drug elicited by drug-paired environmental stimuli. In these paradigms, rodents are trained to self-administer a drug of abuse by exhibiting an instrumental response. Over the course of selfadministration training, drug effects are paired with either the response-contingent presentation of explicit conditioned stimuli (CS) or passive contextual stimulus exposure. Through associative learning processes, these previously neutral stimuli acquire conditioned reinforcing and/or incentive motivational properties, respectively, which permit them to elicit drug seeking in the absence of drug reinforcement (Fuchs et al. 2005; Crombag et al. 2008). Similar to the results from the human neuroimaging studies discussed above, preclinical studies strongly implicate the prefrontal cortex in cue-induced drug seeking. Additionally, these studies suggest that prefrontal cortical subregions exhibit a subregion-specific involvement in mediating drug seeking, depending on the type of cues being utilized and whether drug seeking is assessed following explicit extinction training or after experimenterenforced abstinence.

TTX #

Abstinence Fos ", Arc ", RGS4 ", DAT " BM BM #, TTX #, DA antagonists # –, PL lesion # Lidocaine #, nACh agonist #

Drug priming

BM #, TTX #, D1 antagonist #, D2 antagonist

Stress

Methamphetamine Lidocaine #, nACh agonist # Heroin ania-3 ", MKP-1 ", Fos " zif268 ", c-fos ",Nr4a3 " B/M #" B/M # Ethanol Fos " IL Cocaine Fos " Fos ", pERK " TTX TTX B/M # TTX , BM TTX , BM Methamphetamine Lidocaine Lidocaine Heroin AMPA GluR2 # BM # BM #, CB1 antagonist # OFC Cocaine Arc " Fos " lesion , lOFC: BM #, lesion BM –, TTX , TTX #, lOFC: BM # "mOFC: BM – lOFC: lesion " D1 antagonist #, mOFC: BM mOFC: lesion # D2 antagonist Heroin ania-3 " " denotes an increase, # denotes a decease, and denotes no observed change, in gene or protein expression or in drug-seeking behavior. Abbreviations: ACC anterior cingulate cortex, BM baclofen plus muscimol, CB1 canabinoid 1, DAT dopamine transporter protein, D1 dopamine 1, D2 dopamine 2, IL infralimbic cortex, lOFC lateral orbitofrontal cortex, mOFC medial orbitofrontal cortex, nACh nicotinic cholinergic, p-ERK phospho-extracellular-related kinase, PL prelimbic cortex, RGS4 regulator of G-protein signaling 4, TTX tetrodotoxin

TTX #

Table 1 PFC subregional contribution to drug-seeking behavior Subregion Drug CS/extinction Context/extinction ACC/PL Cocaine Arc ", Fos "

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Relapse Following Extinction

Numerous studies suggest that drug-associated CSs or environmental contexts critically activate regions of the prefrontal cortex to reinstate extinguished drug seeking. CS-induced cocaine seeking is associated with enhanced Fos protein expression in the ACC and enhanced Arc mRNA expression in the ACC, PL, and OFC (Neisewander et al. 2000; Ciccocioppo et al. 2001; Zavala et al. 2008a). Similarly, CS-induced heroin seeking is paralleled by increased mRNA levels for several immediate-early genes, including c-fos, ania-3, MKP-1, and Nr4a3 in the ACC/PL; zif268 in the PL; and ania-3 in the OFC (Schmidt et al. 2005a, b; Koya et al. 2006). Although a cocaine-associated CS fails to alter Fos expression in the IL, cocaine-context re-exposure enhances IL Fos expression in animals that exhibit context-induced drug seeking (Hamlin et al. 2008; Zavala et al. 2008a). Furthermore, drug context-induced ethanol seeking is related to enhanced Fos protein expression in the ACC/PL (Dayas et al. 2007). While changes in immediate-early gene expression are rarely observed in saline-yoked control subjects exposed to cues or in drug-trained subjects not exposed to cues or levers (but see Hamlin et al. 2007), re-exposure to a distinct drug-paired context enhances Fos protein expression in the ACC/PL in rats with a history of passive cocaine, morphine, or nicotine treatment (Franklin and Druhan 2000; Schroeder et al. 2000, 2001; Schroeder and Kelley 2002). Thus, future studies will need to ascertain whether alterations in downstream signaling signify cue-induced incentive motivation or neuroplasticity resulting from drug exposure or behavioral experience, as each of these may influence the involvement of the prefrontal cortex in cue-induced drug seeking.

2.1.1

Anterior Cingulate and Prelimbic Cortex

Performing independent pharmacological manipulations of the ACC and PL has been technically challenging due to the location and proximity of these brain regions. Thus, despite putative differences in connectivity and function, the ACC and PL have not been consistently differentiated in experimental studies of the dorsomedial prefrontal cortex and, as a result, are discussed together here. These pharmacological studies provide direct evidence that the ACC/PL critically regulates cue-induced reinstatement of extinguished drug seeking. McLaughlin and See (2003) first demonstrated that tetrodotoxin (TTX)-induced inactivation of the ACC or PL significantly impairs CS-induced cocaine seeking. Subsequent studies employing lidocaine or baclofen plus muscimol (BM) infusions to achieve neural inactivation have further indicated that the PL mediates CS-induced motivation for methamphetamine and heroin (Hiranita et al. 2006; LaLumiere and Kalivas 2008; Rogers et al. 2008, but see Schmidt et al. 2005a, b). Furthermore, dopamine and acetylcholine neurotransmission in the PL appears to be necessary for CS-induced reinstatement of cocaine and methamphetamine seeking, respectively (Ciccocioppo et al. 2001; Hiranita et al. 2006). In turn, the PL may initiate CS-induced drug

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a

Sensory association Cortex

CS & Context

NBm

BLA

DH ACC VH PL

CeA IL

Motor cortex Spinal cord

Relapse

OFC

VTA

Thalamus dlCPu NAcore VP NAshell

b Drug ACC

VH

PL IL OFC


Relapse

Thalamus

VTA NAcore VP NAshell

c Stress ACC CeA PL LTN

BNST

IL OFC


Thalamus

VTA NAcore VP NAshell

Relapse


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seeking through glutamatergic innervation of the nucleus accumbens core (NAcore) given that BM-induced PL inactivation prevents heroin cue-induced drug seeking and concomitant glutamate release within the NAcore, while AMPA/kainate glutamate receptor antagonism in the NAcore abolishes CS-induced heroin seeking (LaLumiere and Kalivas 2008). Although drug-associated contexts engage a distinct neural circuitry relative to drug-paired CS, TTX-induced ACC/PL inactivation similarly impairs both context-induced and CS-induced cocaine seeking, with the former depending on functional interaction between the ACC/PL and basolateral amygdala (Fuchs et al. 2005, 2007).

2.1.2

Infralimbic Cortex

To date, studies suggest that the IL plays a differential role in CS-induced motivation for different drugs of abuse. While the ACC/PL sends projections to the NAcore, a structure that promotes CS-induced reinstatement of cocaine seeking, the IL preferentially innervates the NAshell, which is not critical for this behavior (Sesack et al. 1989; McFarland and Kalivas 2001; Fuchs et al. 2004a). Consistent with this, IL inactivation achieved through TTX or lidocaine infusions fails to alter CS-induced cocaine or methamphetamine seeking, respectively (McLaughlin and See 2003; Hiranita et al. 2006). However, the neural circuitry underlying CSinduced reinstatement of heroin seeking may engage a wider neural network than that subserving cocaine or methamphetamine seeking. In support of this, BMinduced IL inactivation prevents CS-induced heroin seeking, an effect potentially mediated by cannabinoid 1 receptor stimulation (Rogers et al. 2008; Alvarez-Jaimes et al. 2008). Furthermore, self-administered heroin enhances AMPA receptor internalization in the IL, and this neural adaptation appears to facilitate CS-induced heroin seeking (Van den Oever et al. 2008). While the NAshell is involved in context-induced cocaine seeking, the IL does not mediate this behavior given that TTX inactivation of the IL fails to alter reinstatement elicited by a previously cocaine-paired context (Fuchs et al. 2005, 2008).

< Fig. 1 Schematic illustrating the putative neural circuitries of drug-seeking behavior produced by drug-associated environmental stimuli (a), drug itself (b), and stress (c) in rodent models of drug relapse. The anterior cingulate (ACC), prelimbic (PL), infralimbic (IL), and orbitofrontal (OFC) subregions of the prefrontal cortex differentially contribute to these forms of drug seeking. Black shading denotes a lack of demonstrated contribution to cocaine seeking, whereas gray shading denotes limited contribution. Additional abbreviations: BLA basolateral amygdala, BNST bed nucleus of the stria terminalis, CeA central amygdaloid nucleus, DH dorsal hippocampus, dlCPu dorsolateral caudate-putamen, LTN lateral tegmental nucleus, NAcore nucleus accumbens core, NAshell nucleus accumbens shell, NBm nucleus basalis of Mynert, VH ventral hippocampus, VP ventral pallidum, VTA ventral tegmental area

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2.1.3


Orbitofrontal Cortex

The OFC may play a unique role in drug seeking given that damage to this structure produces irresponsibility, impulsivity, and perseveration in human drug users (Bechara et al. 1994). Moreover, it is a functionally heterogeneous brain region comprised of medial and lateral subregions. Fiber-sparing lesions or BM-induced inactivation of the medial OFC fail to alter CS- or context-induced cocaine seeking. In contrast, BM-induced inactivation of the lateral OFC, which is the putative functional homolog of the human medial OFC, attenuates both CS- and drug context-induced cocaine seeking (Gallagher et al. 1999; Fuchs et al. 2004b; Lasseter et al. 2008). Further, lesions of the lateral OFC made prior to selfadministration training do not alter CS-induced cocaine seeking, but potentiate cocaine-context-induced reinstatement. One possible explanation for these seemingly discrepant findings is that OFC lesion-induced neural adaptations have different effects on cocaine seeking based on cue type (Fuchs et al. 2004b; Lasseter et al. 2008).

2.2

Relapse Following Abstinence

While the previous sections discussed the role of the prefrontal cortex in cueinduced reinstatement of extinguished drug-seeking behavior, human drug users rarely undergo explicit extinction training. Because extinction training is an active learning process that induces neurobiological changes due to learning-induced neuroplasticity, different neural substrates may underlie drug seeking following extinction training versus drug-free abstinence periods (Self and Nestler 1998; Self et al. 2004). For example, while the ACC/PL critically regulates drug seeking following extinction training, its influence is diminished following abstinence without extinction training (Fuchs et al. 2006). Moreover, the duration of the abstinence period may profoundly impact relapse behaviors given that enhanced drug seeking is observed following longer drug-free periods (Tran-Nguyen et al. 1998; Grimm et al. 2001).

2.2.1


Enduring neural adaptations are present in the ACC/PL even after extended abstinence periods, which may be sufficient to facilitate cocaine seeking. After prolonged abstinence, exposure to a cocaine-associated context, discriminative stimuli, and/or CS produces robust cocaine seeking and enhances Fos and Arc expression in the ACC as well as Fos protein expression and dopamine transporter levels in the ACC/PL (Ciccocioppo et al. 2001; Grimm et al. 2002; Schwendt et al. 2007; Hearing et al. 2008). Similar regimens also decrease levels of regulator of G-protein


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signaling 4 in the ACC/PL, which are normalized following re-exposure to a drug-associated context (Schwendt et al. 2007). Fos-mediated cue-induced neuronal activation may involve AMPA glutamate receptor signaling in a subregionspecific manner within the prefrontal cortex because cue-induced cocaine seeking is correlated with significant Fos and GluR1 subunit coexpression in the ACC and Fos and GluR4 subunit coexpression in the IL (Zavala et al. 2007). Thus, cue-induced AMPA receptor-mediated signal transduction in the ACC and IL may involve alternate signaling pathways. In particular, AMPA receptor stimulation in the ACC may facilitate cocaine seeking following abstinence given that systemic AMPA receptor antagonism attenuates this behavior and decreases Fos protein expression in the ACC (Zavala et al. 2008b). Neuroplasticity that occurs in the prefrontal cortex during early abstinence may subsequently promote drug seeking. Consistent with this, acute brain-derived neurotrophic factor (BDNF) administration into the ACC/PL after self-administration training disrupts cue-induced, as well as drug-primed, cocaine seeking following 6 days of abstinence and simultaneously enhances BDNF immunoreactivity and normalizes phospho-extracellularrelated kinase (p-ERK) levels in the NAcore (Berglind et al. 2007).

2.2.2

Infralimbic Cortex

The IL may facilitate cue-induced cocaine seeking following extended abstinence, even though it does not play a critical role in this behavior following extinction training, as discussed above. Re-exposure to cocaine-associated cues increases phosphorylated ERK levels in the IL after 30 days, but not 1 day, of abstinence (Koya et al. 2008). Furthermore, infusions of gamma-aminobutyric acid (GABA) agonists into the IL/PL transition area attenuate, while infusions of GABA antagonists enhance, this behavior following 30 days of abstinence (Koya et al. 2008). However, these effects may be partially mediated by the PL. In contrast, Peters et al. (2008a, b) has reported that GABA agonist-induced IL neural inhibition is sufficient to reinstate cocaine seeking after extended extinction training and also facilitates spontaneous recovery. Hence, while the IL may promote drug seeking following abstinence, it may also be recruited during extinction training to inhibit the same behavior.

2.2.3


Drug-associated cues may recruit the OFC following extended drug-free periods in part via the stimulation of AMPA receptors. After abstinence, the OFC exhibits cue-induced Fos-mediated neuronal activation in conjunction with cocaine seeking, and systemic AMPA receptor antagonism attenuates cocaine seeking and decreases Fos protein expression in the OFC (Zavala et al. 2008b).

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3 Drug-primed Relapse Acute re-exposure to drugs of abuse precipitates drug craving and increases the probability of relapse in abstinent drug users (Jaffe et al. 1989). Similarly, preclinical studies verify that after self-administration and extinction training, an acute drug priming injection elicits robust reinstatement of drug seeking as well as renewal of extinguished conditioned place preference, both of which are thought to reflect motivation for drug. Numerous studies utilizing these animal models further demonstrate that drug-primed drug seeking engages the prefrontal cortex.

3.1


The ACC/PL is critical for the ability of drug-priming injections to reinstate drug seeking for a variety of drugs of abuse, including cocaine, heroin, and methamphetamine (McFarland and Kalivas 2001; Capriles et al. 2003; Hiranita et al. 2006). For instance, ACC/PL inactivation induced by BM or TTX infusions impairs drugprimed heroin and cocaine seeking without producing nonspecific disruption in other goal-directed behaviors (McFarland and Kalivas 2001; Capriles et al. 2003; Rogers et al. 2008). Similarly, selective excitotoxic lesions of the PL attenuate cocaine-primed reinstatement of conditioned place preference (Zavala et al. 2003), while lidocaine-induced inactivation or nicotinic cholinergic receptor stimulation impairs methamphetamine-primed reinstatement (Hiranita et al. 2006). Using functional disconnection techniques, McFarland and Kalivas (2001) have demonstrated that the ventral tegmental area, ACC/PL, NAcore, and ventral pallidum form a serial circuit that mediates cocaine-primed cocaine seeking. While similar circuitry mapping studies have not been conducted for other drugs of abuse, enhanced dopamine neurotransmission in the ACC/PL appears to initiate drug seeking in rats with a history of psychomotor stimulant self-administration. Infusions of dopamine, cocaine, or amphetamine into the ACC/PL can elicit cocaine seeking, while D1 or D2 dopamine receptor antagonists disrupt both cocaine-primed reinstatement of cocaine seeking and conditioned place preference (McFarland and Kalivas 2001; Park et al. 2002; Sanchez et al. 2003; Sun and Rebec 2005; but see Capriles et al. 2003). Studies utilizing in vivo microdialysis suggest that glutamate input from the ACC/PL into the NAcore represents the critical pathway underlying drug-primed reinstatement of drug seeking. While drug priming injections substantially elevate glutamate release in the NAcore, BM-induced ACC/PL inactivation attenuates both cocaine- and heroin-primed drug seeking while simultaneously preventing the increase in glutamate release in the NAcore (McFarland et al. 2003; LaLumiere and Kalivas 2008).


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Infralimbic Cortex

The IL appears to be involved in drug-primed reinstatement in a drug-dependent fashion. It does not mediate psychomotor stimulant-primed reinstatement given that cocaine-primed drug seeking is unimpaired by either BM- or TTX-induced IL inactivation, and methamphetamine-primed reinstatement is not altered by lidocaine infusions into the IL (McFarland and Kalivas 2001; Capriles et al. 2003; Hiranita et al. 2006). Interestingly, however, BM-induced IL inactivation impairs heroin-primed reinstatement of drug seeking, suggesting that drug-primed heroin seeking engenders wider prefrontal cortical recruitment than drug-primed cocaine seeking (Rogers et al. 2008).

3.3


The involvement of the OFC in drug-primed reinstatement of cocaine seeking is unclear. TTX- or BM-induced inactivation of the OFC fails to attenuate cocaineprimed reinstatement (Capriles et al. 2003; Fuchs et al. 2004b). In contrast, lesions of the lateral OFC, but not the medial OFC, increase cocaine-primed reinstatement in a perseverative manner (Fuchs et al. 2004b). This suggests that prolonged loss of lateral OFC output may potentiate cocaine seeking by prompting compensatory neuroadaptations in the drug-primed reinstatement circuitry (Fuchs et al. 2004b).

4 Stress-induced Relapse Psychological stress plays an important role in the initiation and maintenance of drug use. Stress can produce drug craving in current cocaine users under laboratory conditions (Sinha et al. 1999). Similarly, acute stressors, such as footshock, restraint stress, food deprivation, and pharmacological manipulations including corticotrophin-releasing factor, metyrapone, and yohimbine, reliably reinstate drug seeking in laboratory animals after prolonged drug-free periods (Shaham and Stewart 1995; Erb et al. 1996; for review, see Shaham et al. 2000). Both clinical and preclinical studies have implicated the prefrontal cortex in stress-induced relapse behaviors. However, perhaps due to fundamental differences between psychological and acute stress or methodological factors, human neuroimaging studies suggest stress-induced drug craving stems from diminished stress-induced frontal cortical activation in former drug users, while animals studies suggest stressinduced heroin seeking is correlated with enhanced PL Fos protein expression (Shalev et al. 2003; Sinha et al. 2005).

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4.1



Dopamine neurotransmission in the ACC/PL critically mediates stress-induced reinstatement. BM- or TTX-induced inactivation of, as well as dopamine receptor antagonism within, the ACC/PL or PL alone inhibits the ability of footshock and restraint stress to reinstate cocaine seeking or cocaine-conditioned place preference (Capriles et al. 2003; McFarland et al. 2003; Sanchez et al. 2003). Furthermore, it has been theorized that within the larger stress-induced reinstatement circuitry, glutamatergic input from the ACC/PL to the NAcore may initiate stress-induced reinstatement following analysis of inputs from the extended amygdala (McFarland et al. 2003). Stressors are well-known to activate the central noradrenergic system, and this system may play a specific role in mediating drug seeking produced by acute stress. Systemic injections of alpha-2 adrenergic receptor agonists prevent footshockinduced reinstatement of cocaine seeking and inhibit stress-induced norepinephrine release within the ACC/PL (Erb et al. 2000). However, additional research is necessary to explore the direct involvement of ACC/PL norepinephrine release in this behavioral phenomenon.

4.2

Infralimbic Cortex

The IL does not appear to critically regulate stress-induced reinstatement of drug seeking. Neither BM- nor TTX-induced inactivation of the IL alters footshockinduced reinstatement of cocaine seeking (McFarland et al. 2004; Capriles et al. 2003). However, the possible involvement of the IL in the ability of stress to elicit other forms of drug-seeking behavior has yet to be explored.

4.3


Dopamine in the OFC plays a critical role in footshock-induced drug seeking. Consistent with this, TTX-induced inactivation of the lateral OFC impairs footshock-induced reinstatement of cocaine seeking, while intra-OFC microinfusion of D1-like, but not D2-like, dopamine receptor antagonists have a similar effect on this behavior (Capriles et al. 2003).

5 Concluding Remarks Research utilizing rodent models of drug relapse has demonstrated that prefrontal cortical subregions make distinct contributions to relapse behaviors. The ACC/PL exerts critical control over drug seeking elicited by drug-paired CS, contextual


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stimuli, small amounts of drug, and stress following extinction training, but it exhibits diminished involvement in drug seeking following abstinence without extinction. Unlike the ACC/PL, the OFC does not appear to contribute critically to drug-primed reinstatement of drug seeking even though it facilitates cue-induced and stress-induced relapse behaviors. In further contrast to the ACC/PL, the IL appears to play a role in cue-induced drug seeking following abstinence whereas its involvement in cue-induced and drug-primed drug seeking following extinction training is limited to heroin-seeking behavior. Moreover, the IL does not appear to play a significant role in stress-induced relapse behaviors. In addition to the evidence indicating that the functional integrity of the prefrontal cortex is necessary for various forms of drug seeking, intriguing molecular adaptations have been identified within the ACC, PL, OFC, and IL as well as other elements of the relapse circuitry in rats following passive drug exposure, drug-self administration, abstinence or extinction training, as well as in conjunction with drug-seeking behaviors (for review, see Kalivas and O’Brien 2008; Thomas et al. 2008). Thus, from an addiction treatment perspective, it will be imperative to ascertain whether these neuroadaptations have functional significance with respect to relapse behaviors.

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Neural Substrates of Psychostimulant Withdrawal-Induced Anhedonia Manoranjan S. D’Souza and Athina Markou

Contents 1 2 3 4 5

Introduction: Anhedonia and Psychostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Psychostimulant Withdrawal in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Theoretical Perspective on Psychostimulant Withdrawal-Induced Anhedonia . . . . . . . . . . . . 125 Psychostimulant Withdrawal-Induced Anhedonia in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Assessment of Anhedonia in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 5.1 Assessment of Brain Reward Function with the Intracranial Self-Stimulation Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 5.2 Assessing Decreases in Incentive-Motivation for Rewarding Stimuli . . . . . . . . . . . . . . 133 6 Neural Substrates and Psychostimulant Withdrawal-Induced Anhedonia . . . . . . . . . . . . . . . . 136 6.1 Neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 6.2 Neurohormones, Neuropeptides, and Neurotrophic Factors . . . . . . . . . . . . . . . . . . . . . . . . 149 6.3 Neurosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 6.4 Endocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 6.5 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 7 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Abstract Psychostimulant drugs have powerful reinforcing and hedonic properties and are frequently abused. Cessation of psychostimulant administration results in a withdrawal syndrome characterized by anhedonia (i.e., an inability to experience pleasure). In humans, psychostimulant withdrawal-induced anhedonia can be debilitating and has been hypothesized to play an important role in relapse to drug use. Hence, understanding the neural substrates involved in psychostimulant withdrawal-induced anhedonia is essential. In this review, we first summarize the theoretical perspectives of psychostimulant withdrawal-induced anhedonia. Experimental procedures and measures used to assess anhedonia in experimental M.S. D’Souza and A. Markou (*) Department of Psychiatry, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA e-mail: [email protected]


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animals are also discussed. The review then focuses on neural substrates hypothesized to play an important role in anhedonia experienced after termination of psychostimulant administration, such as with cocaine, amphetamine-like drugs, and nicotine. Both neural substrates that have been extensively investigated and some that need further evaluation with respect to psychostimulant withdrawal-induced anhedonia are reviewed. In the context of reviewing the various neurosubstrates of psychostimulant withdrawal, we also discuss pharmacological medications that have been used to treat psychostimulant withdrawal in humans. This literature review indicates that great progress has been made in understanding the neural substrates of anhedonia associated with psychostimulant withdrawal. These advances in our understanding of the neurobiology of anhedonia may also shed light on the neurobiology of nondrug-induced anhedonia, such as that seen as a core symptom of depression and a negative symptom of schizophrenia. Keywords psychostimulants anhedonia dopamine glutamate intracranial self-stimulation serotonin nucleus accumbens mesolimbic pathway

Abbreviations 5-HT Ach ACTH AMPA CRF DA ICSS MDD NAc nAchR NMDA NPY VTA

5-Hydroxytryptamine (serotonin) Acetylcholine Adrenocorticotropic hormone a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Corticotropin-releasing factor Dopamine Intracranial self-stimulation Major depressive disorder Nucleus accumbens Nicotinic acetylcholine receptor N-methyl-D-aspartate Neuropeptide Y Ventral tegmental area

1 Introduction: Anhedonia and Psychostimulants The pleasure associated with an experience or a particular state was termed hedonia in the mid-1600s and is derived from the Greek word hedonikos (De La Garza 2005). The ability to experience pleasure is essential for learning, as well as for our

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mental well-being and social interactions. The inability to experience pleasure, or lack of interest, in rewarding activities was termed anhedonia by French psychologist T. Ribot (Auriacombe et al. 1997). People who cannot experience pleasure are socially withdrawn and lack motivation to carry out their daily activities, and their behavior is not guided by rewards, unlike healthy people. The inability to experience pleasure or lack of interest in rewarding activities can lead to psychological disturbances that characterize psychiatric disorders, such as major depression (Hasler et al. 2004) and schizophrenia (Andreasen 1982). In fact, anhedonia is a core symptom of depression and schizophrenia (American Psychiatric Association 1994). This inability to experience pleasure is hypothesized to be the result of deficits in the functioning of brain reward systems (Nestler and Carlezon 2006). A major class of drugs of abuse that initially induce pleasurable effects in humans are the psychostimulant compounds. Psychostimulants share the common property of activating motoric behavior, and this is why they are often referred to as psychomotor stimulants. Some of the most potent psychostimulants include cocaine, D-amphetamine, and methamphetamine. Nicotine, another widely abused drug in the form of tobacco smoking, is a mild psychostimulant (Grilly 2000) and will also be discussed in this review. Acute administration of these drugs induces euphoria, elation, mood elevation, alertness, focused attention, reduced fatigue, and suppressed appetite (Cami and Farre 2003; Gawin and Ellinwood 1989). The degree to which these effects are produced varies from drug to drug. Notably, however, the general motor activation does not occur in all cases. Patients with attention deficit hyperactivity disorder (ADHD) are treated with psychostimulant compounds, such as methylphenidate, to calm agitated/hyperactive behavior (Arnsten 2006). The powerful stimulation of brain reward systems after administration of psychostimulants results in activation of intrinsic “antireward” or “opponent” mechanisms in an attempt to bring back the deviated hedonic processes (Koob and Le Moal 1997; Solomon and Corbit 1974). These opposing forces are hypothesized to decay slowly, and thus persist for a while even after termination of drug use (Solomon and Corbit 1974). Withdrawal from psychostimulants results in severe affective and psychological morbidity, including anhedonia and somatic symptoms (Barr and Markou 2005; Gawin and Kleber 1986; Hughes and Hatsukami 1986; McGregor et al. 2005; Newton et al. 2004; Watson et al. 1972; Weddington et al. 1990) that are hypothesized to be the result of these opponent mechanisms (Koob and Le Moal 1997). Anhedonia resulting from psychostimulant withdrawal can be incapacitating in some subjects, and anhedonia has been suggested to increase the vulnerability to drug-use relapse in psychostimulant abusers (Leventhal et al. 2008). Hence, to reduce relapse, identifying the neural substrates that play a critical role in psychostimulant withdrawal-induced anhedonia and developing effective pharmacological medications for its treatment are essential. In this review, we will focus on the neural substrates mediating anhedonia seen after cessation of chronic administration of psychostimulant drugs. Additionally, we will discuss animal models used to assess anhedonia. The occurrence of anhedonia in psychostimulant abusers, as well as depressed patients and schizophrenia patients, may reflect

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the fact that some common abnormalities characterize these three disorders that mediate anhedonia (Markou and Kenny 2002; Markou et al. 1998; Paterson and Markou 2007). Thus, investigations of the neural substrates of depressive symptomatology may offer insights into psychostimulant withdrawal-induced anhedonia.

2 Psychostimulant Withdrawal in Humans The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV; American Psychiatric Association 1994) defines substance withdrawal using the following three criteria: (i) the development of a substance-specific syndrome due to the cessation of, or reduction in, substance use that has been heavy and prolonged; (ii) the substance-specific syndrome causes clinically significant distress or impairment in social, occupational, or other important areas of functioning; and (iii) the symptoms are not due to a general medical condition and are not better accounted for by another mental disorder. The signs and symptoms vary depending on the drug, the amount of drug that has been used, the pattern of drug use, and the duration of drug use. Unlike other drugs of abuse, such as alcohol or opioids, in which withdrawal symptoms have a significant physical component, psychostimulant withdrawal has predominantly psychological and affective components. Withdrawal from psychostimulants, such as cocaine, amphetamine, methamphetamine, and nicotine, results in depressive symptoms, such as dysphoric mood, anhedonia, hypersomnolence, fatigue, sadness, suicidal ideation, and general malaise (Coffey et al. 2000; Gawin and Kleber 1986; Hughes 2007; Hughes and Hatsukami 1986; McGregor et al. 2005; Newton et al. 2004; Satel et al. 1991; Watson et al. 1972; Weddington et al. 1990). Subjects also experience increased appetite, anger, anxiety, irritability, agitation, poor concentration, craving, and physical discomfort. Symptoms generally peak in 2–4 days and gradually decrease over time, persisting for a few weeks. Some of the medications used to treat psychostimulant withdrawal in human subjects are listed in Table 1. These medications include dopaminergic uptake blockers (Garattini 1997; Hurt et al. 1997; Margolin et al. 1995; Srisurapanont et al. 1999), dopamine receptor agonists (Giannini et al. 1987, 1989; Gillin et al. 1994; Kampman et al. 2000; Malcolm et al. 1991; Tennant and Sagherian 1987), tricyclic antidepressants (Gawin et al. 1989; Giannini and Billett 1987; Tuma 1993), selective serotonin reuptake inhibitors (Covey et al. 2002; Killen et al. 2000; Saules et al. 2004), selective norepinephrine blockers (Cox et al. 2004), combined serotonin/norepinephrine blockers, noradrenergic and serotonergic receptor blockers (Cruickshank et al. 2008; Kongsakon et al. 2005), 5-HT1A receptor agonists (West et al. 1991), nicotinic acetylcholine receptor (nAchR) agonists (Gonzales et al. 2006; Jorenby et al. 2006; Nides et al. 2006; Shiffman 2008; Shiffman et al. 2006), and compounds that enhance glutamatergic function (Dackis et al. 2005). These studies, however, did not specifically examine whether the test


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Table 1 Clinical studies for the treatment of depressive symptoms during psychostimulant withdrawal in humans Drug of Medication Medication class and Efficacy Reference withdrawal mechanism of action (depressive symptoms) Amphetamine Amitriptyline Tricyclic Y Tuma (1993) antidepressant; norepinephrine uptake blocker Amineptine Antidepressant; Y Garattini (1997); dopaminergic Srisurapanont uptake blocker et al. (1999) Venlafaxine Combined serotonin/ Y McDowell et al. norepinephrine (2000) uptake blocker Reboxetine Antidepressant; Y Cox et al. (2004) selective norepinephrine uptake blocker N Kongsakon et al. Mirtazapine Antidepressant; (2005) noradrenergic (a2) and serotonergic (5HT2 and 5-HT3) receptor blocker Cocaine Bupropion Dopamine uptake Y Margolin et al. blocker (1995) Tennant and Bromocriptine Dopamine D2 receptor Y agonist Sagherian (1987); Giannini et al. (1987) N Gillin et al. (1994) Lisuride Ergot derivative; dopamine D2 receptor agonist N Malcolm et al. Pergolide Dopamine D1/D2 receptor agonist (1991) Hollander et al. Apomorphine Dopamine D2 receptor Y agonist (1990) Amantadine Indirect dopamine Y Tennant and agonist Sagherian (1987); Giannini et al. (1989); Kampman et al. (2000) Desipramine Tricyclic Y Giannini and Billett antidepressant; (1987); Gawin norepinephrine et al. (1989) uptake blocker Propranolol b-adrenoceptor blocker Y Kampman et al. (2001) Modafinil Glutamate-enhancer N Dackis et al. (2005) N Cruickshank et al. Methamphetamine Mirtazapine Antidepressant; (2008) noradrenergic (a2) and serotonergic (5(continued)

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Table 1 (continued) Drug of Medication withdrawal

Nicotine

Nicotine lozenges

Medication class and mechanism of action HT2 and 5-HT3) receptor blocker Nicotine receptor agonist

Efficacy Reference (depressive symptoms)

Varenicline

a4b2 nicotinic receptor partial agonist

N

Fluoxetine

Selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitor

N

Shiffman et al. (2006); Shiffman (2008) Nides et al. (2006); Gonzales et al. (2006); Jorenby et al. (2006) Saules et al. (2004)

N

Covey et al. (2002)

Y

Killen et al. (2000)

Sertraline Paroxetine þ nicotine patch Buspirone

Y

N West et al. (1991) 5-HT1A receptor agonist Bupropion Dopamine uptake N Hurt et al. (1997) blocker Y effective in alleviating depressive symptoms, N not effective in alleviating depressive symptoms, mechanism of action column describes the main action of the drug, and a drug may have more actions than those reported here

compounds treated anhedonia, and most of the clinical studies were not successful in achieving their primary end point, which was to reduce relapse rates. Nevertheless, some studies did show improvement in alleviating some symptoms associated with psychostimulant withdrawal, including depression (Cox et al. 2004; Kampman et al. 2001; McDowell et al. 2000; Tuma 1993). Future clinical studies may need to be better designed in terms of patient selection (i.e., identifying and grouping patients based on symptom severity) and focusing more on specific dysfunctions, such as anhedonia (Geyer and Markou 1995; Hyman and Fenton 2003; Markou et al. 2008). Currently, sparse information is available about the severity and nature of anhedonia in psychostimulant abusers and the correlation of anhedonia with the amount of drug used. Subjective “high” from acute cocaine intoxication in abusers depends on baseline anhedonic symptoms (Newton et al. 2005; Uslaner et al. 1999). The greater the degree of anhedonia, the greater the “high” experienced after termination of cocaine administration. Based on these findings, anhedonic subjects are hypothesized to be more prone to relapse after an initial slip than people who experience less anhedonia during drug withdrawal (Leventhal et al. 2008). Treatment of protracted anhedonia seen in subjects withdrawing from psychostimulants may help in preventing relapse to drug use (Leventhal et al. 2008).


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Unclear, however, is whether the anhedonia seen during withdrawal from psychostimulant drugs is induced by abused drugs or is merely an exacerbation of preexisting anhedonia. No data exist regarding the status of the reward system at baseline or prior to drug use in individuals who become dependent on psychostimulants. Anhedonia has been proposed to be a personality “trait” rather than a “state” (Loas 1996). This hypothesis implies that anhedonia can preexist prior to drug exposure. A high degree of comorbidity exists between major depressive disorder (MDD) and substance dependence disorder (Kessler et al. 1996; Robins and Regier 1991). This high degree of comorbidity is hypothesized to be due to the use of psychostimulants and other drugs of abuse by the anhedonic subjects in attempts to alleviate the underlying brain reward deficit (i.e., self-medication hypothesis; Khantzian 1985, 1997; Markou et al. 1998). In nondrug abusers, the “high” experienced after acute amphetamine intoxication has been shown to be dependent on the presence of baseline anhedonic symptoms (Tremblay et al. 2002, 2005), similar to the “high” experienced by drug users (see above; Leventhal et al. 2008). Subjects who have baseline anhedonic symptoms experience a greater “high” compared with healthy controls. These findings suggest that anhedonic subjects may also be more vulnerable to developing drug dependence, especially psychostimulant dependence (Leventhal et al. 2008).

3 Theoretical Perspective on Psychostimulant WithdrawalInduced Anhedonia Anhedonia experienced during withdrawal from chronic psychostimulant abuse represents a reward deficit that has been theoretically attributed to a breakdown of hedonic homeostasis described by two major theories: “opponent process” theory and “hedonic set-point shift” theory (i.e., allostasis; for extensive discussions of these theories, see Koob and Le Moal 2001; Schulkin et al. 1994; Solomon 1980; Solomon and Corbit 1974). The opponent process theory posited by Solomon and Corbit (1974) postulates that whenever there is a departure from a state of homeostatic neutrality in brain reward systems, opposing processes are initiated in an attempt to bring the disturbed system back to the original state of homeostasis. According to this theory, the opposing processes are sluggish in onset, slow to build up to an asymptote, and slow to decay. Therefore, they can last longer than the effects of the original homeostasis-perturbing event and can result in depression of brain reward system functioning. Thus, excessive stimulation of brain reward systems induced by psychostimulant administration activates opposing processes to counteract this excessive stimulation. After abrupt cessation of psychostimulant exposure, specific brain circuits attempt to return to hedonic homeostasis. However, the winding up of the opposing processes initiated by the exposure to psychostimualants is a slow process, resulting in anhedonia and other psychological disturbances in the patient.

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More recently, another theory, termed hedonic set-point shift theory or allostasis, has been proposed to explain psychostimulant withdrawal-induced anhedonia (Koob and Le Moal 2001). This theory takes a more expanded view of dysregulated hedonic homeostatic balance and involves brain hormonal and stress response systems, in addition to brain reward circuitry. According to this theory, the repeated and prolonged abuse of psychostimulants results in changing of the homeostatic hedonic set point, resulting in a new elevated allostatic state. This new elevated allostatic state requires higher stimulation to lead to the same degree of hedonic pleasure. Both of these theories suggest that the brain reward system, similar to most biological systems, is homeostatically regulated by various neuronal processes. Excessive and prolonged stimulation resulting from prolonged abuse of psychostimulants can result in disturbing homeostasis, thus leading to dysregulation of brain reward circuitry and ultimately to psychopathological states such as anhedonia.

4 Psychostimulant Withdrawal-Induced Anhedonia in Animals Anhedonia-like effects have been observed in animals after administration and subsequent withdrawal from psychostimulants (Fig. 1). Some of the drug treatment regimens used for inducing psychostimulant withdrawal-induced anhedonia are described in Table 2. The first studies on psychostimulant withdrawal used a procedure in which rats received progressively increasing doses of amphetamine (Leith and Barrett 1976, 1980). Subsequent studies showed dose-dependent effects of cocaine (Kokkinidis and McCarter 1990), amphetamine (Kokkinidis et al. 1980), and nicotine (Bozarth et al. 1998) on brain reward function. Similar effects were observed when cocaine was self-administered by the subjects for prolonged periods of time (Kenny et al. 2003b; Markou and Koob 1991, 1992a, b). Psychostimulant withdrawal effects on brain reward function have also been successfully demonstrated with nicotine and amphetamine delivered subcutaneously via osmotic minipumps (Epping-Jordan et al. 1998; Paterson et al. 2000) that release fixed amounts of drug per unit time, thus maintaining constant drug blood levels. With nicotine, withdrawal effects can be induced either by discontinuing the administration of nicotine (i.e., spontaneous withdrawal) or by administering a nAchR antagonist (i.e., precipitated withdrawal; Epping-Jordan et al. 1998). In addition to anhedonia, animals also exhibit other depression-like symptoms during psychostimulant withdrawal, such as decreased locomotor activity, decreased appetite, increased anxiety, decreased grooming behavior, and mild somatic symptoms (Barr and Markou 2005). These anhedonia-like effects seen following psychostimulant withdrawal in animals are reversed by pharmacological agents currently available for depression/anhedonia and/or drug abuse treatment. These pharmacological treatments include the tricyclic antidepressant desipramine (Markou et al. 1992; Paterson et al. 2008b), serotonergic treatments involving the administration of a selective serotonin reuptake inhibitor with or without a


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Fig. 1 Withdrawal from psychostimulants, such as cocaine (a), amphetamine (b), and nicotine (c), induces transient deficits in brain reward function. These reward deficits, reflecting a state of anhedonia, can be quantified through the use of the intracranial selfstimulation (ICSS) procedure. Psychostimulant withdrawalinduced anhedonia is reflected in elevated current intensity reward thresholds for self-stimulation of the posterior lateral hypothalamus. Cocaine, amphetamine, and nicotine figures taken with permission from Markou and Koob (1991), Paterson et al. (2000), and Harrison et al. (2001), respectively. Please note that direct comparisons of the magnitude of the effects cannot be made among all figures. Different stimulation parameters and stimulation hardware systems were used to conduct the studies with cocaine, amphetamine, and nicotine

5-HT1A receptor antagonist (Harrison et al. 2001; Markou et al. 2005; Muscat et al. 1992b), the atypical antidepressant bupropion (Cryan et al. 2003; Paterson et al. 2007), and the dopamine receptor agonist bromocriptine (Markou and Koob 1992a; Figs. 2 and 3).

5 Assessment of Anhedonia in Animals Several paradigms have been used to assess anhedonia in animals that can be broadly divided into those that (i) directly measure the status of the brain reward system or (ii) assess the incentive-motivation for rewarding stimuli.

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Table 2 Treatment regimens used to induce psychostimulant withdrawal-induced anhedonia in experimental animals Location of ICSS Treatment regimen Reference electrode Cryan et al. (2003); Paterson et al. Posterior D-amphetamine (continuous infusion (2000) lateral using subcutaneous osmotic hypothalamus minipump), 5 or 10 mg kg1 day1 for 6 days D-amphetamine administered Markou et al. (2005); Harrison i.p. three times per day (6 a.m., et al. (2001) 12 a.m., 6 p.m.) for 4 days in a rising-dose regimen starting at 1 mg kg1 and stabilizing at 5 mg kg1 (i.e., 1, 2, 3, 4, 5, 5, 5, 5, 5, 5, 5, 5, 5 mg kg1; total dose, 50 mg kg1) Leith and Barrett (1980) D-amphetamine administered i.p. 5 mg kg1 for 7 days followed by 10 mg kg1 for 7 days Leith and Barrett (1976) D-amphetamine administered i.p. three times per day (8 a.m., 2 p.m., 8 p.m.) beginning with a dose of 1 mg kg1 which was increased in 1 mg kg1 steps at each injection so that for the last injection on the fourth day the animal received 12 mg kg1 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 mg kg1; total dose, 78 mg kg1) D-amphetamine administered i.p. Barr et al. (2002) three times per day (9 a.m., 5 p.m., 12 p.m.), starting with a dose of 1 mg kg1 and escalating by 1 mg kg1 for each subsequent dose (doses expressed as salt) for the first 3 days for nine doses. On day 4, subjects received three doses of 10 mg kg1. Animals therefore received a total of 12 injections over the 4 day period (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 10, 10 mg kg1; total dose, 75 mg kg1) Kokkinidis et al. (1980); Predy and Substantia nigra D-amphetamine administered Kokkinidis (1981) 7.5 mg kg1 i.p. with two injections per day separated by 6 h for 10 consecutive days Ventral D-amphetamine administered Borowski and Kokkinidis (1992) tegmental 10 mg kg1 i.p. for 12 consecutive area days (continued)

Neural Substrates of Psychostimulant Withdrawal-Induced Anhedonia Table 2 (continued) Location of ICSS Treatment regimen electrode Cocaine administered 25 mg kg1 i.p. for 18 days or 30 mg kg1 i.p. for 3 days Posterior lateral Cocaine administered as eight hypothalamus injections of 15 mg kg1 i.p. over 9 h Cocaine administered 0.5 mg kg1 as “binge” intravenous selfadministration (3, 6, 12, 24, or 48 h of cocaine self-administration after stabilization of intake at 3 h day1) Cocaine self-administered for a prespecified number of injections (10, 20, 40, or 80 injections; equivalent to 4.94 0.23, 9.88 0.46, 19.64 0.94, or 39.53 1.84 mg kg1). Each injection was 0.25 mg kg1. The time necessary to self-administer the specific number of injections varied between subjects (10 injections, 40 6.9 min; 20 injections, 99 11.9 min; 40 injections, 185 10.9 min; 80 injections, 376 19.9 min) Nicotine administered via osmotic pump with continuous infusion of 3.16 mg kg1 day1 base or 6.32 mg kg1 day1 base for 7, 21, or 28 days

5.1

129

Reference Frank et al. (1992)

Baldo et al. (1999)

Markou and Koob (1991, 1992a, b), Markou et al. (1992)

Kenny et al. (2003a, b)

Harrison et al. (2001), Epping-Jordan et al. (1998), Cryan et al. (2003), Skjei and Markou (2003), Paterson et al. (2007)

Assessment of Brain Reward Function with the Intracranial Self-Stimulation Procedure

Intracranial self-stimulation (ICSS) is a procedure that provides an operational measure of brain reward system function, reflected in reward thresholds. Effects of manipulations, such as stress, social defeat, or psychostimulant withdrawal, on brain reward function can be reliably assessed using the ICSS procedure. ICSS involves the implantation of microelectrodes into discrete brain sites hypothesized to be part of the brain reward circuits, such as the medial forebrain bundle including the posterior lateral hypothalamus (Baldo et al. 1999), ventral tegmental area (VTA; Borowski and Kokkinidis 1992; Frank et al. 1992), and substantia nigra (Predy and Kokkinidis 1981). Among other actions, stimulation of the medial forebrain bundle may activate excitatory inputs to the dopaminergic system and thereby transynaptically excite the brain reward system (Bielajew and Shizgal

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Fig. 2 The atypical antidepressant bupropion, which is approved for smoking cessation by the Food and Drug Administration (FDA), attenuated elevated reward thresholds seen during withdrawal from nicotine. This figure shows intracranial self-stimulation (ICSS) data (mean SEM) expressed as percentage of pretreatment (drug-naive) baseline. Chronic administration of bupropion/saline and nicotine/saline was carried out using subcutaneous osmotic minipumps that delivered drug chronically. Chronic bupropion prevented the elevation in reward thresholds seen during spontaneous nicotine withdrawal after termination of nicotine administration induced by the removal of the minipump that contained nicotine (indicated by the arrowhead). The bupropion/ saline pump was left in place. *p < 0.05, significant difference between the nicotine/saline-treated group and the saline/saline-treated control group. #p < 0.05, significant difference between the nicotine/saline-treated group and the nicotine/bupropion-treated group. Bupropion acts by blocking the uptake of monoamines, such as dopamine and norepinephrine (Figure taken with permission from Paterson et al. 2007)

1986; Yeomans et al. 2000). Although several methods exist to determine brain reward thresholds, the field has settled on the use of primarily two procedures: the rate-frequency curve-shift procedure (Campbell et al. 1985) and the discrete-trial current-intensity procedure (Kornetsky and Esposito 1979; Markou and Koob 1992b). We will describe these two procedures briefly because they are the ones used most extensively in the studies discussed in this review. In the discrete-trial current-intensity procedure, the subject receives a rewarding noncontingent electrical stimulus and has a time-window (i.e., limited hold period) during which the subject can perform an operant response to receive a contingent electrical stimulus identical in all parameters to the noncontingent stimulus. Failure to respond within the limited hold period results in termination of the trial and initiation of an intertrial interval. The current intensity of the noncontingent and contingent stimuli is varied according to the psychophysical method of limits to allow the determination of a current-intensity threshold. The threshold value is defined as the midpoint in microamps between the current-intensity level at which the animal made two or more positive responses out of the three stimulus presentations and the level at which the animal made less than two positive responses at two


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Fig. 3 Serotonergic (fluoxetine + 5-HT1A receptor antagonist) treatment reversed the elevations in brain reward thresholds observed during amphetamine and nicotine withdrawal. (a) Amphetamine withdrawal resulted in elevated thresholds (mean SEM). p-MPPI (3 mg kg1) + fluoxetine (2.5 or 5 mg kg1) dose-dependently lowered the threshold elevations of amphetamine-withdrawing rats. Arrow indicates the time-point at which one of the various treatments was administered. *p < 0.05, significant differences from the corresponding control group. (b) Nicotine withdrawal resulted in elevated reward thresholds (mean SEM). p-MPPI + fluoxetine lowered the threshold elevations of nicotine-withdrawing rats. Arrow indicates the time-point at which one of the various treatments was administered. *p < 0.05, significant differences from the corresponding control group (Figure taken with permission from Harrison et al. 2001)

consecutive intensities. This reward threshold is the current intensity of the stimulation that is perceived as rewarding, and changes in this threshold indicate changes in reward sensitivity and brain reward function. Lowering of thresholds indicates reward enhancement or facilitation, while elevation of thresholds indicates a decrease in brain reward function and may be considered homologous, or at least analogous, to anhedonia-like symptoms seen in humans.

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The rate-frequency procedure involves the systematic manipulation of the frequency of the stimulation and assessment of the rate of responding at each frequency (Campbell et al. 1985; Gallistel and Freyd 1987). This procedure leads to a sigmoidal function, similar to dose–response relationships with pharmacological stimulation. The reward threshold is usually defined as the frequency that supports an arbitrary percentage of the asymptotic level of responding, such as 50 or 75%. Other methods of threshold estimation involve the extrapolation of where a linear extension of the linear part of the rate-frequency curve meets the x-axis (i.e., frequencies are depicted on this axis; Miliaressis et al. 1986). In rats, independent of whether the rate-frequency function or the discrete-trial current-intensity procedure was used, withdrawal from all drugs of abuse, including cocaine (Kokkinidis and McCarter 1990; Markou and Koob 1991), amphetamine (Barr et al. 2002; Leith and Barrett 1980; Paterson et al. 2000), methamphetamine (Hoefer et al. 2006), and nicotine (Epping-Jordan et al. 1998), is associated with impaired brain reward function and elevated brain reward thresholds. The ICSS procedures also provide measures of motor performance by measuring either the latency to respond after the presentation of the noncontingent electrical stimulus in the discrete-trial procedure or the asymptotic rate of responding in the ratefrequency procedure. In the discrete-trial procedure, the noncontingent electrical stimulus signifies the initiation of a trial during which a reward is available to the subject upon performance of the required operant response. Markou and Koob (1992b) showed that the response latency measure, but not the threshold measure, was sensitive to nonspecific motor impairments. Response latency was unaffected during withdrawal from cocaine (Markou and Koob 1991), amphetamine (Paterson et al. 2000; Wise and Munn 1995), or nicotine (Kenny et al. 2003a), indicating that psychostimulant withdrawal is associated with specific impairment of rewardrelated processes. Such specificity is particularly important for nicotine withdrawal in which the presence of somatic signs of withdrawal could affect motor performance, unlike with amphetamine and cocaine that are not characterized by somatic signs. Similarly, in the rate-frequency procedure, changes in reward efficacy result in leftward (reward facilitation) or rightward (reward attenuation) shifts in the rate-frequency function and have been demonstrated to reflect changes in reward sensitivity and not nonspecific motoric effects (Edmonds and Gallistel 1974). In summary, the ICSS paradigm offers one of the best objective and quantitative measures of brain reward system function (Carlezon and Chartoff 2007; Markou and Koob 1993; Nestler et al. 2002). Additionally, ICSS studies in mice (Elmer et al. 2005; Gill et al. 2004; Stoker et al. 2008; Zacharko et al. 1990) can be very useful because genetically modified mice can be used to specifically identify the neurobiological substrates underlying drug withdrawal-induced anhedonia. Importantly, in terms of pharmacological isomorphism (i.e., whether a pharmacological treatment effective in treating the human condition shows a response in the animal model; Geyer and Markou 1995), the predictive validity of this procedure has been established by showing that medications with efficacy in the treatment of depression/anhedonia and/or drug abuse reversed brain reward deficits in rats undergoing withdrawal from cocaine, amphetamine, or nicotine


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(Harrison et al. 2001; Markou et al. 1992; Paterson et al. 2008a). However, the ICSS paradigm is not without its disadvantages. Some of the major disadvantages of this procedure include the need for stereotaxic surgery and the extensive training required before the implementation of experimental manipulations.

5.2

5.2.1

Assessing Decreases in Incentive-Motivation for Rewarding Stimuli Progressive-Ratio Responding for a Natural Reinforcer

The progressive-ratio schedule of reinforcement provides a measure of the motivation to consume a drug (Hodos 1961; Markou et al. 1993; Richardson and Roberts 1996). This procedure assesses the amount of effort that an animal is willing to emit to obtain a reward (e.g., sucrose). Decreases in the amount of effort that the animal emits in a progressive-ratio schedule provides a measure of avolition, that is, lack of motivation, in addition to reinforcement strength (i.e., incentive). A typical training schedule is the following (Hoefer et al. 2006). Animals are initially trained on a fixed-ratio schedule of reinforcement for 1 h daily for 10 days. The requirement for obtaining reinforcement is gradually increased from a fixed-ratio 1 to fixed-ratio 10 over these 10 days. After this fixed-ratio training is completed, animals are placed on a progressive-ratio schedule to obtain the reinforcement, in which the response requirements necessary to receive a single reinforcement increase according to the following progression: [5e0.2 (total rewards +1) 5], resulting in progressive response requirements of 1, 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, 145, 178, 219, 268, etc., to receive a reward. The number of lever presses for each reward continues to increase until the animal fails to obtain the next reward within the allowed time, commonly 60 min. The final completed ratio is defined as the breakpoint. For psychostimulant compounds, such a response progression results in rats reaching a breakpoint within 4–6 h. Rats undergoing withdrawal from amphetamine after a 4-day escalating dose regimen of D-amphetamine exhibited lower breakpoints for sucrose reward compared with saline-treated controls (Barr and Phillips 1999; Orsini et al. 2001). Similar decreases in breakpoints for sucrose were observed after the termination of an escalating dose regimen of methamphetamine (Hoefer et al. 2006). Such decreases in breakpoints likely reflect decreased motivation to obtain reward during psychostimulant withdrawal.

5.2.2

Sucrose Preference/Consumption

Sucrose consumption/preference is another proposed measure of anhedonia (Casarotto and Andreatini 2007; Papp et al. 1991). Sucrose is a natural reinforcer, and reduced preference for a sucrose solution in rats has been hypothesized to reflect

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decreased sensitivity to reward and has been argued to be homologous with anhedonia (Muscat and Willner 1992; Papp et al. 1991). Rats show inverted U-shaped concentration-dependent consumption and preference for sucrose (Muscat et al. 1991). The intake increases as the concentration of the sucrose solution increases, but for very high concentrations the intake is lower. Operant responding for sucrose shows a similar inverted U-shaped function (Guttman 1953). Sucrose consumption/preference typically is monitored by tracking a decrease in consumption of and/or preference for palatable, low-concentration (1%) sucrose solution over repeated tests. Prior to the first sucrose preference test, animals are subjected to 48 h of forced exposure to 1% sucrose solution to habituate them to the sucrose solution and eliminate avoidance of a novel taste due to neophobia. During this initial exposure, sucrose is the only fluid available for consumption. The following 2 days, the rats have free access to food and water. The animals then are submitted to water deprivation for 16 h prior to performing the sucrose preference test. Animals are single-housed, and testing often occurs in the home cage. During the test, two preweighed bottles, one containing tap water and one containing 1% sucrose solution, are presented to the animal for 1 h. The bottles are weighed again after 1 h, and the weight difference is considered to be the rat’s intake from each bottle. The sum of the water and sucrose intake defines total intake, and sucrose preference is expressed as the proportion of sucrose intake to total intake using the following formula: % Preference ¼ (Flavor intake/total intake) 100. After the sucrose preference test, the animals have free access to food and water. After the baseline sucrose preference test, the animals are subjected to an experimental manipulation either in the form of chronic mild stress or psychostimulant treatment. Care must be taken to ensure that the total fluid intake is not significantly different between the experimental groups. The validity of sucrose drinking as a measure of reward sensitivity has been established by several studies (Muscat et al. 1992a, b; Muscat and Willner 1992). The test has been successfully used by some groups to demonstrate anhedonia-like behavior in animals subjected to chronic mild stress (Casarotto and Andreatini 2007; Papp et al. 1991; Sampson et al. 1992; Willner et al. 1992), but not in animals withdrawing from psychostimulants. This test, however, is well known to produce unreliable results – not all studies have found a decrease in sucrose intake in animals subjected to chronic mild stress (Matthews et al. 1995).

5.2.3

Positive and Negative Contrast Procedures

The contrast paradigm is used to study anhedonia by assessing the effect of devaluation or enhancement of incentive value of a sweet solution reinforcer after preexposure to a different concentration of the sweet solution (Barr and Phillips 2002). Two types of contrast procedures include successive negative contrast and successive positive contrast. In the successive negative contrast procedure, animals are initially trained to obtain a reinforcer of a consistent value (e.g., 32% sucrose solution). If this reinforcer is replaced by a reinforcer of a lesser value (e.g., 4% sucrose solution), then animals consume significantly lower levels of the sucrose solution compared


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with animals that only had continual access to the 4% solution. For example, animals are divided into two groups. One group is exposed to and trained on a 32% sucrose solution, and the other group is exposed to and trained on a 4% sucrose solution. Initially, animals are given two 1-h habituation sessions to their respective sucrose solutions in their home cages on alternate days. Animals are then given access to their respective solutions for a 5-min period once per day in the testing apparatus for 10 days or until most rats reach an asymptotic level of consumption of their respective sucrose solutions. Once stable intake is reached, all animals are given access to a 4% sucrose solution for 5 min for the next 8 days. Animals trained on the 32% sucrose solution show decreased intake of the 4% sucrose solution initially compared with animals trained on the 4% sucrose solution for all 10 days. Intake levels return to baseline levels over time. This phenomenon has been widely demonstrated across species, including rodents, primates, and humans (Grigson et al. 1994; Schnorr 1967; Specht and Twining 1999). However, to assess the effect of psychostimulant withdrawal-induced anhedonia, drug treatment is carried out after animals have reached asymptotic levels of intake. Animals withdrawing from an escalating dose regimen of amphetamine showed an exaggerated decrease in intake of the lower-concentration reinforcer (Barr and Phillips 2002). Furthermore, while control animals showed a rapid increase in consumption of sucrose solution, animals undergoing amphetamine withdrawal required a longer time to return to prewithdrawal levels of consumption. Such an effect is interpreted as a decrease in the perception of reward during amphetamine withdrawal. Similarly, amphetamine withdrawal is also associated with a failure to display successive positive contrast (Vacca and Phillips 2005). The procedure for successive positive contrast is similar to that described above, with the exception that animals are initially exposed to and trained on a 4% sucrose solution. Once animals reach an asymptotic level of intake (e.g., after 10 sessions), one of the groups is exposed to a 32% solution (i.e., a shift in incentive value from 4 to 32%). Normal animals show an enhanced intake of the higher-concentration reinforcer. Animals withdrawn from an escalating dose of amphetamine do not show this enhanced intake of the higher-concentration reinforcer (Vacca and Phillips 2005).

5.2.4

Incentive-Motivation for Sexual Reward

Another procedure used to study anhedonia is decreased motivation to approach a sexually receptive conspecific (Barr et al. 1999; Yirmiya 1996). Anhedonic human subjects show significant reductions from previous levels of sexual interest. Further difficulties in sexual functioning are seen in humans suffering from depression (American Psychiatric Association 1994). In this test, male rats are introduced to a cage and allowed to habituate for 5 min. Subsequently, a receptive female rat is introduced, and copulatory behavior is videotaped for 25 min. The following indices are measured: anticipatory precopulatory activity, intromission latency (time to first intromission), ejaculation latency (time from first mount to ejaculation), and number of ejaculations. Rats undergoing amphetamine withdrawal

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exhibited decreased motivation to obtain access (i.e., decreased anticipatory precopulatory activity) to sexually receptive conspecifics, while measures of copulatory activity were not affected (Barr et al. 1999).

5.2.5

Novelty-Induced Conditioned Place Preference

This procedure is based on the principle that rats spend more time in novel environments (Hughes 1965) and interact more with novel objects (Bevins et al. 2002) than familiar environments and objects, presumably because novelty has reinforcing value. This procedure is similar to the conventional place conditioning procedure, with the exception that a novel object is used as a reward, and one side of the two-chamber box is consistently associated with this novel object (Bevins and Bardo 1999). Specifically, the animals are initially placed at the center of a chamber having two distinct end compartments, and the initial compartment preference of the rat is noted. The animal is then restricted to the nonpreferred compartment with a novel object (i.e., conditioning against a preference is carried out). The animals are similarly restricted to the preferred chamber but without an object. During the postconditioning test in the absence of an object, animals prefer the side associated with a novel object. Withdrawal from nicotine blocked the acquisition of conditioned place preference for novelty reward (Besheer and Bevins 2003). This blockade occurred in the absence of underlying deficits in information processing, such as interactions with an object, novelty detection, environmental familiarization, and expression of learning. This procedure has not been used with other psychostimulant drugs, such as cocaine or amphetamine. The predictive validity of this procedure, in terms of pharmacological isomorphism, has not yet been assessed.

6 Neural Substrates and Psychostimulant Withdrawal-Induced Anhedonia The mesocorticolimbic dopaminergic pathway is one of the critical reward pathways in the brain mediating the reinforcing effects of both natural and unnatural rewards (Koob 1992; Wise 1978). All psychostimulant drugs exert their reinforcing actions partly by activating this reward pathway. More recently, studies have also shown that this pathway plays an important role in reward anticipation and seeking (Nicola et al. 2005; Pessiglione et al. 2006; Schultz 1998). One characteristic of anhedonia is the lack of reward anticipation and seeking. Evidence suggests that dysregulation of the mesocorticolimbic brain reward pathway plays an important role in depression and its constituent symptoms, such as anhedonia (Bressan and Crippa 2005; Di Chiara et al. 1999; Nestler and Carlezon 2006; Shirayama and Chaki 2006). Thus, dysregulation of the mesocorticolimbic reward pathway may


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play an important role in the anhedonia seen during withdrawal from psychostimulant drug exposure. The mesocorticolimbic dopaminergic system consists of dopaminergic neurons originating in the VTA that project to limbic and cortical areas, such as the nucleus accumbens (NAc), prefrontal cortex, amygdala, hippocampus, lateral hypothalamus, entorhinal cortex, and lateral septal area (Beckstead et al. 1979; Fallon and Moore 1978; Lindvall and Stenevi 1978). The NAc is composed of small populations of g-aminobutyric acid (GABA) and cholinergic interneurons, in addition to a large number (about 90%) of efferent GABAergic medium spiny projecting neurons (Chang et al. 1982; Meredith et al. 1993). The mesolimbic dopaminergic neurons are influenced either at the level of the cell body in the VTA or at their terminals in the NAc, or both, by projections from several brain areas. For example, NAc neurons receive excitatory glutamatergic projections from the lateral hypothalamus, prefrontal cortex, amygdala, and hippocampus (Brog et al. 1993; Geisler and Zahm 2005; Kelley and Domesick 1982; Kelley et al. 1982; McDonald 1991; Rosin et al. 2003; Sesack and Pickel 1992). They also receive serotonergic projections from the raphe nucleus, noradrenergic projections from the locus coeruleus (LC), and cholinergic inputs from the pedunculopontine (PPTg) and laterodorsal tegmental nucleus (LDT; Forster and Blaha 2000; Oakman et al. 1995; Omelchenko and Sesack 2006; Overton and Clark 1997; Phillipson 1979; Semba and Fibiger 1992). Furthermore, several peptidergic nuclei arising in the hypothalamus also influence the mesocorticolimbic dopaminergic system (Hsu et al. 2005; Mignot 2004; Saito et al. 1999). The output of the NAc is in the form of GABAergic projections to the VTA/substantia nigra, ventral pallidum, hypothalamus, amygdala, and interpenduncular nucleus (Groenewegen and Russchen 1984; Heimer et al. 1991; Nauta et al. 1978). The various neurotransmitter systems, such as dopaminergic, glutamatergic, GABAergic, adrenergic, cholinergic, and serotonergic, regulate the mesolimbic system through an array of presynaptic and postsynaptic receptors. These projections from the hypothalamus, prefrontal cortex, amygdala, and hippocampus to the mesolimbic reward pathways contain emotional, contextual, and motivational information and thus modulate the response of the mesolimbic system to appetitive and aversive stimuli (Faure et al. 2008; Hyman and Malenka 2001; Hyman et al. 2006). In short, the mesocorticolimbic system is affected by a complex interplay of many neurotransmitters, neurohormones, and other neuromediators. These influences play an important role in regulating this pathway, and disturbances in these neurotransmitter systems and/or receptors or downstream mediators have a possible role in the anhedonia seen during withdrawal from psychostimulants after prolonged use. In the sections below, the roles of each neurotransmitter system that are likely to be involved in psychostimulant-induced anhedonia are discussed (Table 3). In many cases, the potential role of altered neurotransmission in mediating anhedonia is not known, with the exception of inferences made from the temporal correlation of the neurochemical and behavioral events associated with drug withdrawal. Some studies, however, have investigated the direct contribution of specific neurotransmitter changes in anhedonia.

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Table 3 Changes in neural substrates associated with psychostimulant withdrawal Neurotransmitter Change Psychostimulant Reference Dopamine Decreased basal Cocaine, Broom and Yamamoto extracellular dopamine amphetamine, (2005), Imperato et al. levels in the NAc nicotine (1992), Hildebrand et al. (1998), Rahman et al. (2004), Rada et al. (2001), Rossetti et al. (1992), Weiss et al. (1997), Parsons et al. (1991) Decreased firing of VTA Cocaine, Ackerman and White dopaminergic neurons amphetamine, (1992), Henry et al. nicotine (1989), Liu and Jin (2004) Decreased density of Cocaine Pilotte et al. (1994), dopamine transporter Sharpe et al. (1991) Cocaine Macedo et al. (2004), Decreased dopamine D1 receptor binding in the Stefanski et al. (1999) NAc and dorsal striatum Increased dopamine D2 Cocaine Macedo et al. (2001), receptor binding in the Macedo et al. (2004) striatum and premotor cortex Cocaine Neisewander et al. (2004) Increased dopamine D3 receptor binding in the NAc Serotonin Decreased serotonin levels Cocaine, Parsons et al. (1995, in the NAc, striatum, amphetamine, 1996), Persico et al. hippocampus, and methamphetamine (1995), Schmidt et al. prefrontal cortex (1985), Tonge (1974) Cocaine, nicotine Baumann and Rothman Increased sensitivity of (1998), Suemaru et al. 5-HT2A/2C (2001), Yasuda et al. (2002) Cocaine Parsons et al. (1995), Increased sensitivity of Yan et al. (2000) presynaptic 5-HT2A receptors Baumann and Rothman Decreased sensitivity of 5- Cocaine (1998) HT1A receptors Norepinephrine Decreased norepinephrine Amphetamine Vogel et al. (1985) levels in the frontal cortex, hypothalamus, and caudate Decreased a2 receptor Cocaine Giralt and Garcia-Sevilla binding (1989) Upregulation of Cocaine Beveridge et al. (2005), norepinephrine Macey et al. (2003) transporter levels in the bed nucleus of the stria terminalis, basolateral amygdala, cortex, hypothalamus, and hippocampus of primates (continued)

Neural Substrates of Psychostimulant Withdrawal-Induced Anhedonia Table 3 (continued) Neurotransmitter Change Glutamate Decreased extracellular glutamate Increased AMPA receptor subunits GluR1 and GluR2 in the NAc Increased NMDA receptor subunits NR1, NR2A, and NR2B in the NAc, VTA, central nucleus of the amygdala, basolateral amygdala, and frontal cortex Reduced phosphorylation of NR1 in the frontal cortex Decreased mGluR5 in the NAc Increased mGluR5 mRNA in the NAc shell and dorsal striatum Increased mGluR8 mRNA in the NAc and dorsal striatum GABA Increased GABA levels and turnover rate

Decreased mRNA of the b3 subunit of the GABAA receptor in the cortex and caudate putamen Increased parvalbuminpositive neurons Neurohormones, Increased CRF levels in neurothe hypothalamus peptides, and amygdala neurotrophic Increased levels of factors prodynorphin mRNA in the striatum

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Psychostimulant Cocaine, amphetamine Cocaine

Reference Baker et al. (2003), Giorgetti et al. (2002) Lu et al. (2003)

Cocaine

Crespo et al. (2002), Lu et al. (2003, 2005), Loftis and Janowsky (2000)

Cocaine

Loftis and Janowsky (2002)

Cocaine, amphetamine Cocaine

Mao and Wang (2001), Swanson et al. (2001) Ghasemzadeh et al. (1999)

Amphetamine

Parelkar and Wang (2008)

Cocaine, amphetamine

Cocaine

Dworkin et al. (1995), Lynch and Leonard (1978), Xi et al. (2003) Suzuki et al. (2000)

Amphetamine

Mohila and Onn (2005)

Cocaine

Erb et al. (2004), Gardi et al. (1997), Richter and Weiss (1999) Andersson et al. (2003), Isola et al. (2008), Spangler et al. (1993), Turchan et al. (1998) Wahlestedt et al. (1991)

Cocaine, amphetamine, nicotine

Decreased NPY levels in Cocaine the NAc and prefrontal cortex Increased BDNF in the Cocaine NAc

Grimm et al. (2003)

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6.1 6.1.1


Neurotransmitters Dopamine

Dopamine plays a critical role in mediating the rewarding effects of all drugs of abuse, including psychostimulants. Withdrawal from psychostimulants results in a decrease in dopaminergic tone. Specifically, microdialysis studies show decreased basal levels of dopamine in the NAc during withdrawal from psychostimulants, such as cocaine (Imperato et al. 1992; Parsons et al. 1991; Robertson et al. 1991; Rossetti et al. 1992), amphetamine (Broom and Yamamoto 2005; Rossetti et al. 1992; Weiss et al. 1997), and nicotine (Hildebrand et al. 1998; Rada et al. 2001; Rahman et al. 2004). Consistent with decreased dopamine levels in the NAc, decreased activity of mesolimbic dopaminergic neurons also occurs during withdrawal from psychostimulants (Ackerman and White 1992; Henry et al. 1989; Liu and Jin 2004). Withdrawal from cocaine results in a decrease in the density of dopaminergic transporter levels (Pilotte et al. 1994; Sharpe et al. 1991), and withdrawal from cocaine and amphetamine-like drugs results in decreased density and sensitivity of dopamine D1 receptors (Macedo et al. 2004; Stefanski et al. 1999, 2002). Rats exposed to chronic nicotine treatment exhibit decreased sensitivity to the ICSS threshold-elevating effects of the dopamine D1 receptor antagonist SCH 23390 administered into the anterior VTA compared with saline-treated control rats, while the response to the D2-like receptor antagonist eticlopride was unaltered (Bruijnzeel and Markou 2005). These findings indicate a downregulation in the number or function of D1 receptors after chronic nicotine administration. Additionally, upregulation of dopamine D2 receptors in the striatum have been reported during withdrawal from cocaine (Macedo et al. 2004). Finally, increases in dopamine D3 receptor binding in the NAc core have been reported during withdrawal from cocaine self-administration (Neisewander et al. 2004). Several pharmacological manipulations aimed at correcting the deficits in dopaminergic neurotransmission seen during psychostimulant withdrawal have been effective in reversing psychostimulant withdrawal-induced anhedonia in animal models, thus implicating these deficits in the mediation of anhedonia. Increasing dopaminergic neurotransmission by using a dopamine reuptake blocker, such as bupropion, alleviates the elevation of ICSS thresholds seen during withdrawal from nicotine (Cryan et al. 2003; Paterson et al. 2007). However, the lowering of ICSS thresholds was also seen in saline controls, suggesting that the effect of bupropion is nonspecific (i.e., statistically additive) and related to the reward-facilitating effects of bupropion independent of the “allostatic baseline” state of the animals. Importantly, bupropion has other mechanisms of action, such as inhibition of norepinephrine uptake, which may also play a role in the “therapeutic” properties of bupropion. Bromocriptine, a dopamine D2 receptor agonist, also reversed ICSS threshold elevations observed in rats undergoing cocaine withdrawal (Markou and Koob 1992a). Clinically, bupropion alleviated cocaine withdrawal symptoms only in a subset of patients who reported depressive symptomatology at the beginning of the


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study (Margolin et al. 1995). Bromocriptine alleviated dysphoria associated with cocaine withdrawal in human subjects (Giannini et al. 1987; Tennant and Sagherian 1987). Nevertheless, more recent studies generally did not demonstrate efficacy of bromocriptine in alleviating the affective aspects of cocaine withdrawal (Eiler et al. 1995; Handelsman et al. 1997). Bromocriptine, in combination with the tricyclic antidepressant desipramine, was successful in attenuating symptoms of cocaine withdrawal, indicating that bromocriptine may be most effective as an adjunct therapy. The dopamine D2 receptor agonist apomorphine rapidly reversed depressive symptomatology observed during cocaine withdrawal in humans (Hollander et al. 1990). The indirect dopamine agonist amantadine has also proven to be more effective than direct agonists at treating symptoms of cocaine withdrawal (Giannini et al. 1989; Tennant and Sagherian 1987), particularly when used in patients with severe withdrawal symptoms (Kampman et al. 2000). Altogether, these results suggest that the dopaminergic system is critically involved in anhedonia seen during psychostimulant withdrawal.

6.1.2

Serotonin

Both acute and chronic administration of psychostimulants leads to adaptive changes in the brain serotonergic system (Carrasco and Battaglia 2007; Cunningham et al. 1992a, b; Hoplight et al. 2007). Importantly, the serotonergic system is a critical neurotransmitter system for the action of currently used antidepressant medications, such as selective serotonin reuptake inhibitors (Ban 2001). Thus, serotonin is likely to play an important role in psychostimulant withdrawal-induced anhedonia. Deficits in serotonergic transmission have been observed during psychostimulant withdrawal. Withdrawal from psychostimulants results in decreased serotonin levels in the NAc (Parsons et al. 1995, 1996) and other brain regions, such as the hippocampus, striatum, and prefrontal cortex (Persico et al. 1995; Schmidt et al. 1985; Tonge 1974). Impaired serotonin release in response to fenfluramine has been reported during cocaine withdrawal (Baumann et al. 1995; Benwell and Balfour 1979; Darmani 1997). Withdrawal from psychostimulants also results in changes in serotonergic receptor sensitivity. Specifically, withdrawal from cocaine is associated with an increased prolactin response to systemic administration of 5HT2A/2C receptor agonists and a decreased response to a 5HT1A receptor agonist, suggesting an increased sensitivity of postsynaptic 5HT2A/2C receptors and decreased sensitivity of 5HT1A receptors (Baumann and Rothman 1998). A similar increase in sensitivity of 5HT2A/2C receptors has also been observed during withdrawal from nicotine (Suemaru et al. 2001; Yasuda et al. 2002). Withdrawal from chronic cocaine is also associated with an increase in sensitivity of presynaptic 5-HT2A receptors, and intra-NAc application of serotonin or a 5HT2A receptor agonist increased dopamine overflow in withdrawing rats, presumably attributable to an increased sensitivity of these 5HT2A receptors (Parsons et al.

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1995; Yan et al. 2000). Finally, withdrawal from nicotine resulted in increased sensitivity of 5-HT1A receptors located in the dorsal raphe (Rasmussen and Czachura 1997). Reversal of serotonergic deficits by coadministration of the selective serotonin reuptake inhibitors fluoxetine or paroxetine and the 5HT1A receptor antagonist p-MPPI (4-[20 -methoxy-phenyl]-piperazine) reversed ICSS threshold elevations seen in animals withdrawing from amphetamine or nicotine (Harrison et al. 2001; Markou et al. 2005). However, administration of either compound alone had no effect on threshold elevations. Surprisingly, coadministration of fluoxetine and p-MPPI elevated ICSS thresholds in saline-exposed control rats, an effect opposite to that seen in psychostimulant-withdrawing animals (Harrison et al. 2001; Harrison and Markou 2001). Furthermore, although fluoxetine and p-MPPI attenuated reward deficits associated with nicotine withdrawal, the combined effect had no effect on the somatic signs of nicotine withdrawal, providing evidence for different mechanisms underlying these two components of nicotine withdrawal. Reversal of threshold elevations during withdrawal from nicotine or amphetamine was also achieved by chronic administration of the atypical antipsychotic clozapine (Semenova and Markou 2003; Fig. 4). Clozapine has a mixed pharmacological profile and exhibits high affinity for several subtypes of serotonin receptors (5-HT2A, 5-HT2C, 5-HT6, 5-HT7), dopamine receptors (D2, D4), muscarinic receptors (M1), and adrenergic receptors (a1; Goudie et al. 1998; Meltzer 1994; Zhang and Bymaster 1999). Evidence suggests that the antagonistic properties of clozapine at 5-HT2A and D4 receptors are critical for the clinical actions of clozapine (Meltzer 1994).

6.1.3

Norepinephrine

Another neurotransmitter that may play an important role in mediating anhedonia during psychostimulant withdrawal is the norepinephrine system. The brain noradrenergic system comprises two main ascending projections: the dorsal noradrenergic bundle (DNB) and the ventral noradrenergic bundle (VNB). The DNB originates in the A6 area of the LC and projects to the hippocampus, cerebellum, VTA, and forebrain. The VNB arises in a number of pons and medulla nuclei and innervates the hypothalamus, midbrain, and extended amygdala (Moore and Bloom 1979). The firing of midbrain dopaminergic neurons, which form the mesolimbic dopaminergic system, is influenced by noradrenergic projections from the LC (Grenhoff et al. 1993; Liprando et al. 2004). The noradrenergic pathways support ICSS (Ritter and Stein 1974), and drugs acting on the noradrenergic system can modulate ICSS thresholds (Wise 1978). Additionally, the biochemical effects of psychostimulants include blockade of norepinephrine reuptake and enhancement of norepinephrine release, or both (Holman 1994; Howell and Kimmel 2008; Weinshenker and Schroeder 2007). The actions of several clinically effective antidepressant medications, such as imipramine and desipramine, are mediated via inhibition of norepinephrine reuptake (Richelson and Pfenning 1984). This evidence


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Fig. 4 Clozapine, an atypical antipsychotic with activity predominantly involving serotonergic and dopaminergic systems, was administered to rats prior to inducing spontaneous nicotine withdrawal. The figure shows that clozapine administration blocked threshold elevations (defined as 10% or more above baseline) in 50% of rats 6 h following termination of nicotine administration. Clozapine pretreatment (before any exposure to nicotine) by itself resulted in elevations of reward thresholds in some animals, and these animals were termed clozapine-sensitive rats. These clozapine-sensitive rats showed greatest threshold elevations during nicotine withdrawal. Hence, the right panel of graphs shows data in which rats sensitive to the initial mildly aversive effects of clozapine pretreatment were excluded. Fisher’s exact test revealed significantly fewer rats showing withdrawal after clozapine pretreatment compared with vehicle-pretreated rats when clozapine- or vehicle-sensitive rats were excluded (*p < 0.05). Numbers in parentheses are the total number of rats per group. clz clozapine, n nicotine, s saline, v vehicle (Figure taken with permission from Semenova and Markou (2003))

strongly suggests an involvement of the norepinephrine system in psychostimulant withdrawal-induced anhedonia. Norepinephrine levels are decreased in several brain regions, such as the frontal cortex, hypothalamus, caudate, and pons-medulla, during withdrawal from chronic amphetamine administration (Vogel et al. 1985). Changes in norepinephrine function have also been observed following chronic psychostimulant administration. After chronic cocaine exposure, decreased binding of the a2-adrenoceptor agonist clonidine occurs in the rat cortex and hypothalamus (Giralt and Garcia-Sevilla 1989). Rats chronically treated with cocaine showed a decreased mydriatic response to clonidine (Pitts and Marwah 1989). Chronic cocaine administration was also associated with desensitization of postsynaptic a2 adrenoceptors coupled with growth hormone secretion (Baumann et al. 2004). Chronic cocaine also resulted in upregulation of norepinephrine transporter levels in the bed nucleus of the stria terminalis (Macey et al. 2003), basolateral amygdala, cortex, hypothalamus, and hippocampus of primates (Beveridge et al. 2005). The tricyclic antidepressants desipramine and imipramine, which act by blocking norepinephrine reuptake (Richelson and Pfenning 1984), attenuated

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elevations in ICSS thresholds associated with cocaine and amphetamine withdrawal, respectively (Kokkinidis et al. 1980; Markou et al. 1992). Specifically, repeated daily administration of desipramine shortened the duration of ICSS threshold elevations associated with cocaine withdrawal in rats. Such an effect was correlated with b-adrenoceptor downregulation (Markou et al. 1992), suggesting that altered norepinephrine signaling mediated anhedonia associated with cocaine withdrawal. Consistent with this finding, the b-adrenoceptor blocker propranolol decreased cocaine withdrawal severity in humans (Kampman et al. 2001). Kokkinidis et al. (1980) showed that treatment with either amitriptyline or imipramine counteracted depressed responding for self-stimulation of the substantia nigra seen during amphetamine withdrawal. Chronic, but not acute, administration of desipramine prevented ICSS threshold elevations and prevented increases in somatic signs observed during nicotine withdrawal (Paterson et al. 2008a; Fig. 5). This pattern of results suggests that b-adrenoceptor downregulation (Markou et al. 1992) or some other neuroadaptations induced by chronic desipramine administration is critical for the antianhedonic effect of desipramine. Additional actions of desipramine that may contribute to its antianhedonic properties include noncompetitive blockade of N-methyl-D-aspartate (NMDA) receptors (Sernagor et al. 1989; Watanabe et al. 1993) and nAchRs (Izaguirre et al. 1997; Rana et al. 1993). Further work is necessary to clarify which actions of desipramine mediate the reversal of anhedonia. As mentioned above, bupropion also attenuated elevations in ICSS thresholds seen during nicotine withdrawal (Cryan et al. 2003; Malin et al. 2006; Paterson et al. 2007). In addition to its action on the dopamine system, bupropion also acts as a norepinephrine transporter inhibitor (Damaj et al. 2004; Ferris et al. 1983) and exhibits low levels of dopamine transporter occupancy at therapeutic levels (Learned-Coughlin et al. 2003; Meyer et al. 2002) while enhancing norepinephrine turnover (Golden et al. 1988a, b). These observations raise the possibility that the effects of bupropion on the noradrenergic system could be more important than its effects on the dopamine transporter in its antismoking properties.

6.1.4

Glutamate

Glutamate is the major excitatory neurotransmitter, and acute administration of psychostimulants, such as cocaine, amphetamine, and nicotine, increases glutamate release in both the NAc and VTA (Reid et al. 2000, 1997; Smith et al. 1995; Xue et al. 1996). Chronic administration of psychostimulants leads to adaptations in the glutamatergic system (Lu et al. 2005, 2003; Swanson et al. 2001), and these adaptations may play a critical role in psychostimulant withdrawal-induced anhedonia. Increasing evidence suggests that glutamatergic substrates play a role in the pathophysiology of depression. NMDA receptor antagonists have antidepressantlike effects in animal models of depression (Paul and Skolnick 2003). Ketamine, an NMDA receptor antagonist, produces rapid, but transient, antidepressant effects in human subjects suffering from depression (Berman et al. 2000; Krystal 2007). This rapid action of ketamine may be useful in reversing anhedonia in subjects


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Fig. 5 Chronic desipramine (DMI) prevented brain reward threshold elevations during nicotine withdrawal. The figure shows the effects of chronic DMI (15 mg kg1 day1, salt, administered via osmotic minipumps) treatment on brain reward thresholds measured using the intracranial selfstimulation (ICSS) procedure. Brain reward thresholds (mean SEM) during nicotine/saline withdrawal expressed as percent of prenicotine/saline baseline thresholds. *p < 0.05, **p < 0.01, significant differences from the saline/vehicle group. #p < 0.01, significant difference from the nicotine/DMI group (p < 0.05)

withdrawing from psychostimulants and may provide a major advantage over conventional antidepressants that take approximately 3–6 weeks to be effective (Frazer and Morilak 2005). The above evidence makes a strong case for the evaluation of glutamate in psychostimulant withdrawal-induced anhedonia. Withdrawal from chronic cocaine and amphetamine resulted in a decrease in extracellular mesolimbic glutamate levels (Baker et al. 2003; Giorgetti et al. 2002). Together with the decrease in mesolimbic extracellular glutamate levels, several studies have also reported changes in AMPA and NMDA receptors. An increase in the AMPA glutamate receptor subunits GluR1 and GluR2 and the NMDA receptor subunit NR1 in the NAc have been observed during cocaine withdrawal (Crespo et al. 2002; Loftis and Janowsky 2000; Lu et al. 2003). Increases in NMDA and AMPA subunits have also been seen during cocaine withdrawal in the VTA (NR1 and GluR2), central nucleus of the amygdala (NR1 and GluR2), and basolateral amygdala (GluR1, NR2A, and NR2B; Lu et al. 2003, 2005). Cocaine withdrawal is also associated with reduced phosphorylation of serine residues 896 and 897 of the NMDA NR1 subunit in the frontal cortex (Loftis and Janowsky 2002). Furthermore, microinjection of AMPA into the VTA during amphetamine withdrawal enhanced the release of glutamate and dopamine in the VTA, suggesting an enhancement in AMPA receptor expression in the VTA (Giorgetti et al. 2001). However, not all studies have reported an increase in NMDA and AMPA receptors during cocaine withdrawal. Some studies report decreases in the levels of

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NMDA and AMPA receptor subunits during amphetamine and cocaine withdrawal (Lu et al. 1999; Lu and Wolf 1999; Yamaguchi et al. 2002). These discrepancies appear to be mainly attributable to the time-point at which brain tissue was collected following cessation of cocaine or amphetamine administration (early [24 h] vs. late [14, 30, 90 days]) and the experience of the animals following withdrawal (extinction vs. nonextinction training). In addition to changes in ionotropic receptors, changes in metabotropic receptors also occur after termination of chronic psychostimulant administration. Specifically, group I metabotropic glutamate receptors are downregulated (Swanson et al. 2001), including mGluR1 and mGluR5, and mGluR5 mRNA is upregulated (Ghasemzadeh et al. 1999) during cocaine withdrawal. A recent study showed that cocaine withdrawal resulted in a decrease in membrane-bound mGluR1, especially in large dendrites of the NAc (Mitrano et al. 2008). Repeated cocaine also prolonged the decrease in mGluR2/3 function in the NAc (Xi et al. 2002). A transient increase in mGluR1 levels and a prolonged decrease in mGluR5 levels in the NAc have also been reported during amphetamine withdrawal (Mao and Wang 2001). A more recent study suggested that mGluR8 mRNA levels in the NAc and dorsal striatum are elevated during amphetamine withdrawal (Parelkar and Wang 2008). Withdrawal from nicotine is also associated with impaired glutamatergic neurotransmission (for review, see Kenny and Markou 2001; Markou 2007). Systemic administration or microinjection of the mGluR2/3 receptor agonist LY354740 into the VTA precipitated ICSS threshold elevations in chronically nicotine but not saline-treated rats, suggesting that mGlu2/3 receptors mediate the anhedonic aspects of nicotine withdrawal (Kenny et al. 2003a). Administration of the mGluR2/3 receptor antagonist LY341495 attenuated ICSS threshold elevations associated with nicotine withdrawal (Kenny et al. 2003a). Reward deficits seen during nicotine withdrawal were also attenuated by coadministration of the mGluR2/3 antagonists LY341495 and MPEP (Liechti and Markou 2007). With regard to changes in ionotropic and glutamatergic receptors during withdrawal from psychostimulants, compounds opposing these changes may be effective in reversing psychostimulant withdrawalinduced anhedonia.

6.1.5

GABA

GABA is the major inhibitory neurotransmitter in the mammalian brain and plays an important role in the negative regulation of brain reward function. The GABA transaminase inhibitor g-vinyl GABA, which increases GABA levels, dose-dependently elevated brain reward thresholds (Kushner et al. 1997). This effect is hypothesized to be mediated by the GABAB receptor. Systemic administration of the GABAB receptor agonist CGP 44532 elevated ICSS thresholds, presumably by enhancing GABAergic neurotransmission via postsynaptic GABAB receptors (Macey et al. 2001). However, systemic administration the GABAB receptor antagonists CGP 56433A or CGP 51176 also elevated brain


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reward thresholds (Macey et al. 2001). GABAB receptor antagonists are suggested to elevate reward thresholds by enhancing GABA release by acting on presynaptic GABAB receptors (Macey et al. 2001). Thus, negative modulation of brain reward function via the GABAB receptor is complex. Both agonists and antagonists at this receptor show negative modulation of reward, presumably depending on activation of postsynaptic or presynaptic GABAB receptors, respectively. Evidence also suggests that MDD is associated with dysfunction of GABAergic transmission (Brambilla et al. 2003; Krystal et al. 2002; Lloyd et al. 1989), and pharmacological agents modulating GABAergic transmission show antidepressant-like activity in animal models of depression. For example, the GABAB receptor positive allosteric modulator CGP 7930, the GABAB agonists baclofen and SKF 97541, and GABAB antagonists SCH 50911 and CGP 56433A all showed antidepressant-like activity in preclinical animal models (Frankowska et al. 2007; Mombereau et al. 2004). Moreover, evidence suggests that the GABAergic system negatively regulates the rewarding effects of psychostimulants. The GABAB receptor positive modulator GS39783 attenuated the reward-facilitating effects of cocaine (Slattery et al. 2005), and the GABAB receptor positive allosteric modulator BHF177 decreased the reward-facilitating effects of nicotine (Paterson et al. 2008b) measured by ICSS. Withdrawal from cocaine resulted in increased extracellular GABAergic content in the NAc core (Xi et al. 2003). These increased GABA levels were attributable to desensitization of presynaptic GABAB autoreceptors that play an important role in regulating synaptic GABA levels. Another study also reported an increase in GABA turnover rate upon withdrawal from cocaine (Dworkin et al. 1995). Cocaine withdrawal resulted in decreased mRNA of the GABAA receptor b3 subunit in the cortex and caudate putamen (Suzuki et al. 2000). In the same study, 1 week of withdrawal from cocaine increased mRNA expression of the a1 and b3 subunits of the GABAA receptor in the frontal cortex and hippocampus. In a more recent study, rats undergoing withdrawal from cocaine showed increased pentobarbital-induced sleep time (Ma et al. 2008). This study also found increased GABAA receptor a subunit levels and increased glutamic acid decarboxylase levels in the hypothalamus during cocaine withdrawal. Similarly, GABA concentrations were increased in the amygdala during withdrawal from amphetamine (Lynch and Leonard 1978). Finally, increased GABAergic interneurons immunoreactive for the calcium binding protein parvalbumin were found in the anterior cingulate cortex during amphetamine withdrawal (Mohila and Onn 2005). This latter finding is interesting because a recent postmortem study of patients with a history of depression found a decrease in parvalbumin-positive neurons in the dorsolateral prefrontal cortex (Rajkowska et al. 2007). The GABAergic system is also involved in mediating anxiety (Pilc and Nowak 2005). Thus, changes in the GABAergic system following chronic administration of psychostimulants and subsequent withdrawal may mediate anxiety symptoms, rather than depression/anhedonia, seen during psychostimulant withdrawal (Murphy et al. 2001). However, the negative regulation of reward function by GABAergic compounds and the antidepressant effect of GABAergic agents suggest that

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further exploration of the role of the GABAergic system in psychostimulant withdrawal-induced anhedonia is needed.

6.1.6

Acetylcholine

Acetylcholine is another neurotransmitter that plays an important role in regulating the mesocorticolimbic reward circuit (Calabresi et al. 2000; Clarke and Pert 1985; Zhou et al. 2003a). Evidence suggests that the cholinergic system contributes to the reinforcing effects of psychostimulants. For example, the acetycholinesterase inhibitor physostigmine decreased cocaine self-administration (de la Garza and Johanson 1982). The nAchR antagonist mecamylamine blocked the heightened dopaminergic response and psychomotor effects of cocaine-induced sensitization (Schoffelmeer et al. 2002). In humans, stimulation of the central cholinergic system with cholinomimetics or cholinesterase inhibitors induced depressive phenotypes, including depressed mood, dysphoria, and anhedonia (Dilsaver 1986). Depressed human subjects are hypersensitive to a cholinergic challenge compared with healthy control subjects (Dilsaver 1986). Anticholinergic agents, such as antimuscarinic (Chau et al. 2001) and antinicotinic compounds (Shytle et al. 2002; Slemmer et al. 2000), have antidepressant activity. Many conventional antidepressants have nAChR antagonist properties (Izaguirre et al. 1997; Rana et al. 1993; Shytle et al. 2002). nAChR blockade is suggested to be crucial to the antidepressant effects of the tricyclic antidepressant amitriptyline in mice (Caldarone et al. 2004). Altogether, these observations suggest that acetylcholine may play a role in psychostimulant withdrawal-induced anhedonia. However, nAChR antagonists precipitate the affective, somatic, and neurochemical components of nicotine withdrawal in rodents chronically treated with nicotine (Epping-Jordan et al. 1998; Hildebrand et al. 1998, 1999). Thus, nAChR blockade is highly unlikely to attenuate ICSS threshold elevations associated with nicotine withdrawal. However, nicotine withdrawal may be mediated by hyperfunctioning of nAchR receptors. The nAChR antagonist mecamylamine did not improve nicotine withdrawal in human smokers (Rose et al. 2001). Nicotine and nicotine receptor agonists (a4b2) also showed antidepressant activity (Ferguson et al. 2000; Semba et al. 1998) similar to nAchR antagonists (see above). To our knowledge, no studies have evaluated the effects of anticholinergic agents on anhedonia during psychostimulant withdrawal. Interestingly, however, high rates of tobacco smoking are observed in depressed patients compared with the general population (Aubin et al. 1996), supporting the hypothesis that nAchR activation with nicotine contained in tobacco smoke may be useful as self-medication of depressive symptoms (Markou et al. 1998). Altogether, the anticholinergic effect of currently available antidepressants and the regulation of the mesolimbic reward pathway by cholinergic neurons suggest that acetylcholine may be an important substrate that needs further evaluation with respect to psychostimulant withdrawalinduced anhedonia.


6.2

149

Neurohormones, Neuropeptides, and Neurotrophic Factors

Several neuropeptides originating in the hypothalamus play a critical role in mediating mood, stress, and hedonia. These include corticotropin-releasing factor (CRF), vasopressin, melanin concentrating hormone (MCH), melanin stimulating hormone (MSH), and orexin. Other neuropeptides, such as opioids, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF), have also been found to play a critical role in the pathophysiology of depression. Changes in these neuropeptides have been reported following psychostimulant administration. Although much work is still required to assess the role of these mediators in psychostimulant withdrawal-induced anhedonia, we will discuss them here as possible mediators needing further evaluation. CRF is a 41-amino acid peptide that controls hormonal and behavioral responses to stressors (Turnbull and Rivier 1997). It is synthesized in the paraventricular nucleus of the hypothalamus and induces the release of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary. ACTH in turn stimulates glucocorticoid synthesis and secretion from the adrenal cortex. The hypothalamus, anterior lobe of the pituitary gland, and adrenal gland together form the hypothalamic-pituitary-adrenal (HPA) axis. In addition to the hypothalamic CRF system, CRF immunoreactivity has also been found in the neocortex, extended amygdala, medial septum, thalamus, cerebellum, and autonomic midbrain and hindbrain nuclei (Swanson et al. 1983). Evidence also suggests that extrahypothalamic CRF systems play an important role in drug dependence and withdrawal (for review, see Koob 2008). The HPA axis plays an important role in mediating stress (Koob 2008), and thus CRF levels can be expected to rise during stressful events, such as psychostimulant withdrawal. Increased levels of CRF have been reported in the hypothalamus and amygdala during cocaine withdrawal (Erb et al. 2004; Gardi et al. 1997; Richter and Weiss 1999; Zhou et al. 2003b). Although increased CRF levels may contribute significantly to anxiety associated with cocaine withdrawal (Basso et al. 1999), intracerebral infusion of only relatively large CRF doses have resulted in increased ICSS thresholds (Macey et al. 2000), indicating a possible role for elevated CRF levels in anhedonia. A recent study by Bruijnzeel et al. (2007) showed that a systemic CRF1 receptor antagonist blocked elevations of ICSS thresholds in animals undergoing nicotine withdrawal precipitated by injection of the nAchR antagonist mecamylamine (Bruijnzeel et al. 2007). However, the CRF1 antagonist did not block elevations of brain reward thresholds seen during spontaneous nicotine withdrawal. This discrepancy may be due to the time at which the CRF1 antagonist was administered. During precipitated withdrawal, the CRF1 antagonist was administered 30 min before administration of the nAchR antagonist. During spontaneous withdrawal, the CRF1 antagonist was administered 6 h after removal of nicotinereleasing osmotic pumps. Thus, the CRF1 antagonist is hypothesized to block the initiation of brain reward deficits, but not to reverse the deficit once the process is initiated (Bruijnzeel et al. 2007).

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The nonpeptide vasopressin is another neuromediator mainly known for its role in fluid metabolism. It also plays a role in regulating the HPA axis and stress adaptation (Aguilera and Rabadan-Diehl 2000). Vasopressin is released from the posterior lobe of the pituitary, and extrahypothalamic vasopressin-containing neurons have been identified in the rat medial amygdala and bed nucleus of the stria terminalis (Caffe et al. 1987). Vasopressin acts on V1a and V1b vasopressin receptors expressed mainly in limbic areas and the hypothalamus (Lolait et al. 1995). Vasopressin is hypothesized to play an important role in the pathophysiology of depression. Abnormalities in vasopressin expression and receptor function have been found in both clinical depression and genetic animal models of depression (Keck et al. 2003; Zhou et al. 2001). Furthermore, the nonpeptide V1b receptor antagonist SSR149415 exerted antidepressant-like effects in rodents (Griebel et al. 2002). Blockade of V1b receptors in the lateral septum and central nucleus of the amygdala have been shown to play an important role in mediating the antidepressant effects of this compound (Salome et al. 2006; Stemmelin et al. 2005). Recent evidence suggests that vasopressin may also be involved in mediating the negative affect associated with drug withdrawal. Specifically, the V1b antagonist blocked the aversive effects of heroin withdrawal (Zhou et al. 2008), and increased vasopressin mRNA levels have been observed during cocaine withdrawal (Zhou et al. 2005). The role of vasopressin in regulating stress and the HPA axis, and the antidepressant effects of a V1b antagonist, suggest that vasopressin may be an important substrate of psychostimulant withdrawal-induced anhedonia. MCH is another neuropeptide that has received much attention in depression and hedonia associated with food reward (Saper et al. 2002). Increasing evidence suggests that melanin may play a role in the regulation of mood and stress (Nestler and Carlezon 2006; Shirayama and Chaki 2006; Smith et al., 2009). It is synthesized by neurons in the lateral hypothalamus that have extensive projections throughout the brain and play a role in regulating the mesolimbic reward pathway (Bittencourt et al. 1992; Smith et al. 2005). Melanin acts through MCH1 and MCH2 G-protein-coupled receptors. The MCH1 receptor shows dramatic enrichment in the NAc (Saito et al. 1999), and several MCH1 receptor antagonists administered systemically or directly into the NAc have exhibited antidepressant-like effects (Borowsky et al. 2002; Georgescu et al. 2005). Although studies evaluating the role of MCH in drug reward are generally lacking, one study has shown that MCH may play a role in mediating the effects of cocaine. Mice lacking MCH1 did not show locomotor sensitization or a conditioned increase in locomotor activity after cocaine treatment (Tyhon et al. 2006). Melanocortins are another group of neuromediators mainly involved in regulating appetite (Fan et al. 1997). Melanocortins are synthesized by proopiomelanocortin (POMC)-expressing neurons in the arcuate nucleus in the hypothalamus (Adan et al. 2006). The melanocortins consist of a, b, and g MSHs. Increasing evidence suggests an interaction between melanocortins and the mesolimbic pathway. For example, microinjection of a melanocortin agonist into the VTA increased NAc dopamine levels (Lindblom et al. 2001). The melanocortin receptor agonist MTII enhanced the effects of amphetamine on ICSS thresholds (Cabeza de Vaca et al. 2002). The key


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receptor through which melanocortins act is the MC4 receptor, which is widely distributed in the NAc (Alvaro et al. 1996; Hsu et al. 2005). Nonpeptide MC4 receptor antagonists showed some antidepressant-like effects in animal models (Chaki et al. 2003). Evidence suggests that melanocortins and the MC4 receptor system play a role in mediating psychostimulant reward, especially cocaine reward. For example, repeated cocaine administration enhanced melanocortin levels in the brain (Sarnyai et al. 1992; Tong and Pelletier 1992) and upregulated MC4R mRNA in the NAc (Alvaro et al. 2003). MC4 knockout mice do not show locomotor sensitization upon repeated cocaine administration (Hsu et al. 2005). Presently, however, no evidence has supported the role of melanocortin neuropeptides during psychostimulant withdrawal. Orexin (hypocretin) is another peptide produced by neurons located in the perifornical area of the lateral hypothalamus that appears to play a critical role in appetite regulation, arousal, motivation, and stress (Boutrel et al. 2005; Koob 2008; Mignot 2004; Sakurai et al. 1998). Orexin neurons project extensively throughout the brain (Peyron et al. 1998), and orexin A and orexin B are the two currently known orexin peptides. These peptides act via orexin-1 (OX1) and orexin-2 (OX2) receptors (Sakurai et al. 1998). Orexin neurons regulate the mesolimbic system by providing strong innervation to the dopaminergic neurons in the VTA via the OX1 receptor, and thus regulate reward, including drug reward (Korotkova et al. 2003; Nakamura et al. 2000). Orexin peptides have been implicated in the modulation of noradrenergic (Horvath et al. 1999), cholinergic (Burlet et al. 2002), and serotonergic (Brown et al. 2001, 2002) systems and the HPA axis (Jaszberenyi et al. 2000; Kuru et al. 2000). Orexin plays a critical role in regulating sleep–wake cycles, and orexin deficiency causes narcolepsy. Patients with narcolepsy have a high incidence of depression (Daniels et al. 2001). Abnormalities in orexin signaling are hypothesized to be related to the sleep abnormalities reported in depression (Allard et al. 2004). However, infusion of orexin A in the lateral ventricle or VTA elevated ICSS thresholds, indicating a decrease in excitability of brain reward systems (Boutrel et al. 2005). This effect is similar to that seen after intracerebroventricular infusion of CRF (Macey et al. 2000) or during drug withdrawal (Epping-Jordan et al. 1998; Markou and Koob 1991). Chronic cocaine administration upregulated OX2 receptor protein levels in the NAc (Zhang et al. 2007). The effect of orexin receptor agonists and antagonists on psychostimulant withdrawal-induced anhedonia should be evaluated. Endogenous opioids are another important group of neuromediators. Three distinct families of endogenous opioid peptides have been identified, including endorphin, dynorphin, and enkephalin. These endogenous peptides act on m, k, and d receptors, respectively, which are widely distributed throughout the brain (Bodnar 2007). Dynorphin has the greatest affinity for k receptors. Endorphins have equal affinity for m and d receptors. Enkephalins have higher affinity for d receptors. Opioid receptors distributed along the mesolimbic system play a critical role in modulating the reinforcing properties of psychostimulant drugs (Corrigall et al. 1999; Kuzmin et al. 1998; Ward and Roberts 2007). Much focus has been on k opioid receptors in mediating dysphoria and the negative affective states associated

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with psychostimulant withdrawal. Upregulation of the dynorphin system is hypothesized to mediate the dysphoria and negative emotional symptoms experienced by humans during cocaine withdrawal (Shippenberg et al. 2007). In rats, withdrawal from cocaine (Andersson et al. 2003; Spangler et al. 1993), amphetamine (Turchan et al. 1998), and nicotine (Isola et al. 2008) is associated with increased levels of prodynorphin mRNA (the precursor for dynorphin) in the striatum. k receptor agonists induced a conditioned place aversion in mice (McLaughlin et al. 2006) and dysphoria and depression in humans (Pfeiffer et al. 1986). The k receptor agonist U69593 dose-dependently elevated ICSS thresholds, reflecting a decrease in brain reward function (Todtenkopf et al. 2004). More recently, U69593 antagonized the lowering of ICSS thresholds induced by acute cocaine administration (Tomasiewicz et al. 2008). k opioid receptor antagonists on their own did not influence brain reward function assessed in the ICSS procedure (Todtenkopf et al. 2004). However, k receptor antagonists have antidepressant-like effects in the forced swim test (Mague et al. 2003; McLaughlin et al. 2003). To date, however, no study has evaluated the effects of k receptor antagonists during psychostimulant withdrawal. Enkephalin, another opioid peptide that acts mainly on the d opioid receptor, is reported to play a role in reward processes in proenkephalin knockout mice (Skoubis et al. 2005). The d receptor agonist SNC80 has demonstrated antidepressant activity (Broom et al. 2002; Saitoh et al. 2004). However, the effects of these compounds on psychostimulant withdrawal remain to be evaluated. NPY is a 36-amino acid peptide that is expressed extensively in the brain, including the LC, hypothalamus, amygdala, hippocampus, NAc, and neocortex (Adrian et al. 1983; Larhammar et al. 1998). Central NPY colocalizes with norepinephrine, GABA, somatostatin, and agouti-related protein (Kask et al. 2002). The CNS effects of NPY are mediated through Y1, Y2, Y4, Y5 heterogeneous G-proteincoupled receptors (Kask et al. 2002). Extensive evidence suggests that NPY plays a critical role in depression and mood disorders. In humans, NPY levels in cerebrospinal fluid are lower in depressed patients compared with healthy controls (Heilig et al. 2004; Widerlov et al. 1988). Clinically effective antidepressant treatments (e.g., repeated electroconvulsive therapy and the selective serotonin reuptake inhibitor fluoxetine) elevated brain NPY levels in rats (Baker et al. 1996; Heilig et al. 1988; Stenfors et al. 1989). In animals, centrally administered Y1 receptor agonists have antidepressant-like effects (Redrobe et al. 2002; Stogner and Holmes 2000). Cocaine withdrawal resulted in significant reductions in NPY levels in the NAc and cortex (Wahlestedt et al. 1991). A study investigating the role of NPY in brain reward function, however, showed that both NPY and a Y1 agonist failed to attenuate the elevations in brain reward threshold associated with precipitated nicotine withdrawal (Rylkova et al. 2008). However, NPY and the Y1 receptor agonist [D-His26]-NPY reduced the somatic signs of nicotine withdrawal. The same study also showed that NPY decreased the rewarding effects of ICSS, and this effect was mediated via Y1 receptor-dependent mechanisms. BDNF is a member of the nerve growth factor family (Barde et al. 1982). In addition to neuronal development and survival, BDNF is hypothesized to play an important role in learning, motivation, and mood regulation (Lipsky and Marini


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2007). BDNF signal transduction is mediated by binding to two different transmembrane receptors, the high-affinity tyrosine kinase receptor B (TrKB), which specifically recognizes BDNF, and the low-affinity p75 neurotrophin receptor (Klein et al. 1991). BDNF is expressed in many brain sites, including the amygdala (Rattiner et al. 2004), striatum (Yurek et al. 1996), and prefrontal cortex (Bland et al. 2005). The TrKB receptor is expressed in all mesencephalic dopaminergic neurons (Numan and Seroogy 1999). Evidence suggests that BDNF plays an important role in depression and the mode of action of antidepressants. Specifically, serum BDNF levels are low in patients suffering from depression (Karege et al. 2002) and return to normal levels upon treatment with antidepressants (Shimizu et al. 2003). However, the role of BDNF in depression and antidepressant action in animal models depends on the brain region involved. For example, repeated stress, which can lead to depression-like effects in animals, decreased BDNF levels in the hippocampus (Duman and Monteggia 2006). Injection of BDNF in the hippocampus led to antidepressant-like effects (Shirayama et al. 2002). Intra-VTA BDNF exerted a depression-like effect in the forced swim test, and blockade of BDNF action in the NAc using viral-mediated overexpression of dominant negative mutant TrkB induced an antidepressant-like effect in the NAc in the same test (Eisch et al. 2003). BDNF also plays an important role in psychostimulant reinforcement and withdrawal. BDNF administered directly into the VTA or NAc led to a profound increase in cocaine reward in several behavioral paradigms (Filip et al. 2006; Horger et al. 1999; Lu et al. 2004). Increases in BDNF have been reported in the NAc during cocaine withdrawal (Grimm et al. 2003). However, significant increases were also seen at 30 and 90 days of cocaine withdrawal, and these increases are unlikely to be associated with anhedonia that is most commonly observed during early cocaine withdrawal. Further work is necessary to understand the role of BDNF in psychostimulant withdrawal-induced anhedonia and other depressive symptoms.

6.3

Neurosteroids

Neurosteroids are neuromediators that may play a role in mediating psychostimulant withdrawal-induced anhedonia. Neurosteroids are synthesized from cholesterol and include 3a-hydroxy compounds (e.g., pregnenolone, dihydroepiandrosterone [DHEA], and their sulfate derivatives [DHEA-S]) and metabolites of progesterone (e.g., 3a-hydroxy-5a-pregnan-20-one, also known as allopregnanolone; (Corpechot et al. 1993). In the brain, in addition to their traditional action via nuclear receptors, both gonadal steroids and neurosteroids show rapid, nongenomic, and stereospecific steroid actions transmitted via specific membrane receptors, such as GABAA, ionotropic glutamate, and sigma receptors (Falkenstein et al. 2000; Jung-Testas et al. 1989). DHEA-S has shown antidepressant effects in both humans and animals (Maayan et al. 2005; Wolkowitz et al. 1997). Levels of DHEA and DHEA-S are altered following cocaine abuse. In hospitalized chronic cocaine users, discontinuation (1–3 weeks) of cocaine resulted in increased plasma cortisol levels that were highest at the beginning of abstinence and then subsequently decreased, whereas

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levels of DHEA-S were low at the beginning of abstinence and increased later (Buydens-Branchey et al. 2002). In another study of cocaine abusers (3 weeks of inpatient therapy for cocaine dependence and 10-week follow-up), significantly lower levels of DHEA-S were observed in abusers who relapsed (Shoptaw et al. 2004; Wilkins et al. 1997). Another study also showed that only patients in whom spontaneous increases in DHEA-S levels were observed were successful at abstaining from cocaine use over time (Wilkins et al. 2005). Wilkins et al. (2005) suggested that increased circulating DHEA-S levels result in improved mood, and this effect may enhance resiliency during withdrawal. A recent study in smokers, however, did not find differences in brain DHEA-S between those who relapsed within 4 weeks of their quit date and those who remained abstinent (Ceballos and al’Absi 2006).

6.4

Endocannabinoids

The endocannabinoid system consists of endogenous ligands, cannabinoid receptors, and several proteins/enzymes responsible for their synthesis and degradation. The role of the endocannabinoid system on hedonic activity has been evaluated using the ICSS procedure. The CB1 receptor agonists WIN 55,212, HU210, and CP55940 dose-dependently elevated brain reward thresholds, indicating an inhibitory influence of these drugs on brain reward mechanisms (Vlachou et al. 2005). A fatty acid amide hydrolase inhibitor and a selective anandamide uptake inhibitor, both of which increase endocannabinoid levels, also inhibited the rewarding effects of electrical brain stimulation (Vlachou et al. 2006). The CB1 receptor agonist WIN 55,212-2 reversed the threshold-lowering effects of cocaine, whereas pretreatment with the CB1 antagonist SR141716A reversed the inhibitory effects of WIN 55,212 on cocaine-induced lowering of brain reward thresholds (Vlachou et al. 2003). Thus, the CB1 receptor agonist blocked the reward-facilitating effects of cocaine. Endocannabinoids appear to negatively regulate brain reward, and endocannabinoid receptor antagonists may facilitate reward and alleviate psychostimulant withdrawal-induced anhedonia. However, one study showed that the CB1 antagonist SR141716A (1–10 mg kg1, i.p.) decreased the reinforcing value of electrical medial forebrain bundle stimulation, supporting a facilitatory role for endogenous cannabinoids in brain reward function (Deroche-Gamonet et al. 2001). The reason for this discrepancy is not clear, and further work is necessary to evaluate the role of the cannabinoid system on hedonic activity, and especially its effect during psychostimulant withdrawal-induced anhedonia.

6.5

Cytokines

Although not traditionally associated with psychostimulants or psychostimulant withdrawal, increasing evidence suggests interactions between immune signaling molecules, such as cytokines, and the brain (Connor et al. 1998; Sugama et al. 2004).


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Cytokines are also hypothesized to play a critical role in major depression and the mode of action of currently available antidepressants (Dunn et al. 2005; Kenis and Maes 2002; Leonard 2000; Maes 2008; Raison et al. 2009). A recent study showed that monocytes in cocaine-dependent subjects have a decreased capacity to express tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), which are important for activating the immune system in the fight against pathogens (Irwin et al. 2007). During cocaine withdrawal, proliferative responses of peripheral blood lymphocytes in response to stimulation by mitogen concanavalin A were decreased, indicating a suppression of the immune system in response to stress resulting from the cessation of cocaine administration (Avila et al. 2003, 2004). Furthermore, lipopolysaccharide (LPS)-induced secretion of proinflammatory cytokines was suppressed following treatment with the amphetamine-derivative 3,4-methylenedioxymethamphetamine (MDMA, which is not actually classified as a psychostimulant but rather as an entactogen; Nichols 1986), shifting T-cell cytokine production away from a T-helper 1 (Th1) direction and toward Th2 (Connor 2004; Connor et al. 2005), similar to results found with cocaine (Stanulis et al. 1997). To our knowledge, no studies have yet determined the effects of psychostimulant withdrawal on cytokine levels in the brain. Because stress is associated with increased levels of cytokines in the brain (Nguyen et al. 2000), and peripheral administration of cytokines can induce affective states such as anhedonia (Anisman and Merali 1999; Asnis and De La Garza 2005; De La Garza 2005; but see Dunn et al. 2005), further examination of psychostimulant withdrawal-induced anhedonia and the immune system is required.

7 Summary and Conclusions Anhedonia, the inability to experience pleasure, is a core symptom of psychostimulant withdrawal and a core symptom of psychiatric disorders, such as depression and schizophrenia (American Psychiatric Association 1994). The existence of a high degree of comorbidity between psychopathological conditions, such as depression and schizophrenia, with drug dependence suggests that some drug abusers may have some form of subclinical anhedonia that they attempt to ameliorate by using drugs of abuse, such as psychostimulants (Khantzian 1985; Markou et al. 1998). Thus, abuse of psychostimulants and their subsequent withdrawal may result in anhedonia not only from a de novo perturbation of the normal hedonic state but also from a worsening of preexisting subclinical anhedonia. Anhedonia during psychostimulant withdrawal is hypothesized to increase vulnerability of the individual to drug use relapse (Leventhal et al. 2008). Therefore, understanding the neurobiological substrates that mediate this state is essential. In this review, we described several methods used to assess anhedonia and incentive-motivation in animals, such as the ICSS procedure, the progressiveratio schedule for sucrose reward, sucrose preference tests, positive and negative

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contrast tests, incentive-motivation for sexual reward, and novelty-induced conditioned place preference. Psychostimulant withdrawal-induced anhedonia models described in this review have high etiological validity in which the etiology of the condition is identical in humans and experimental animals, good construct validity in cases in which a dependent measure is used that accurately and reliably assesses the construct of anhedonia, and predictive validity in which treatments effective in treating anhedonia in humans have been shown to be effective in the models. Several classes of antidepressant medications, such as monoamine oxidase inhibitors, tricyclic antidepressants, and selective serotonin reuptake inhibitors, are all effective in reversing brain reward deficits seen in animals during psychostimulant withdrawal (Harrison et al. 2001; Paterson et al. 2008a). Thus, considering all of the aforementioned features, psychostimulant withdrawal-induced anhedonia in animals is a well-validated animal model that can be used to understand the neurobiological substrates of reward and motivational deficits in humans. Although animal procedures can be used to quantify anhedonia in experimental animals, this is not the case for most assessments of anhedonia in humans. Most frequently, with few exceptions (e.g., Pizzagalli et al. 2005, 2008), anhedonia is measured in humans using subjective tests (Leventhal et al. 2006). Furthermore, none of the established methods of assessing anhedonia in animals or humans have an exact parallel that can be used for measuring anhedonia in the other species. To improve the success of compounds that preclinical studies suggest may have efficacy in treating anhedonia in patients (i.e., translational predictability), a desperate need exists to develop methods or tests for anhedonia that can be used both in humans and animals (Markou et al. 2008). Additionally, potential clinical treatments have been used as magic bullets, with the expectation that they will prevent relapse while simultaneously alleviating all symptoms associated with psycho-stimulant withdrawal. This magic bullet approach may need to be reevaluated, and future studies may need to adopt multiple strategies to prevent relapse, including focusing on specific symptoms, such as psychostimulant withdrawalinduced anhedonia (Hyman and Fenton 2003; Markou et al. 2008). In this chapter, we reviewed the current knowledge on the neural substrates of anhedonia. Some of these substrates, such as monoamine neurotransmitters (dopamine, serotonin, and norepinephrine) have been extensively studied. A great deal of evidence suggests that a decrease in extracellular levels of monoamine neurotransmitters during psychostimulant withdrawal directly modulate anhedonia (Parsons et al. 1991, 1996; Rada et al. 2001; Rahman et al. 2004; Rossetti et al. 1992). In addition to a decrease in monoamine levels, dysregulation also occurs in the functioning of receptors that mediate monoaminergic neurotransmission (Baumann et al. 1995; Bruijnzeel and Markou 2005; Stefanski et al. 2002; Suemaru et al. 2001). Several typical and atypical antidepressants and other compounds that act on the monoaminergic system reverse the anhedonia-like effects of psychostimulant withdrawal in animals (Harrison and Markou 2001; Paterson et al. 2007). In addition to monoamines, disturbances in neuronal signaling mediated via amino acid neurotransmitters, such as glutamate and GABA, have also been reported during psychostimulant withdrawal (Baker et al.


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2003; Xi et al. 2003). Several metabotropic glutamatergic receptor compounds have been shown to positively or negatively regulate anhedonia-like effects in animals (for review, see Markou 2007). GABAergic compounds have not yet been directly evaluated in psychostimulant withdrawal-induced anhedonia. In addition to these classical neurotransmitters, several neuromediators, such as neurohormones and neuropeptides, are receiving greater attention primarily because of their role in stress, depression, and psychostimulant-induced or food reward. These include CRF, orexin, melanocortins, MCH, vasopressin, opioids, BDNF, and NPY (Boutrel 2008; Koob 2008; Nestler and Carlezon 2006; Shirayama and Chaki 2006). Among these, CRF1 receptor antagonists have been shown to reverse anhedonia-like effects of nAchR antagonist-precipitated nicotine withdrawal (Bruijnzeel et al. 2007). Similarly, neurosteroids, cannabinoids, and cytokines are potential substrates of anhedonia, based primarily on studies that have evaluated their role in depression and psychostimulant reward (Boutrel 2008; Raison et al. 2008; Wolf and Kirschbaum 1999). However, the functional significance of these neural substrates in mediating psychostimulant withdrawal-induced anhedonia remains to be determined. In conclusion, withdrawal from psychostimulants results in an anhedonic state that can increase the vulnerability of an individual to drug use relapse. Identifying the neural substrates and molecules whose abnormal functioning may be responsible for the induction and maintenance of this state is imperative, and attempting to alleviate this state by developing pharmacological medications aimed at normalizing the functioning of these substrates will be important. Furthermore, some of the substrates involved in psychostimulant withdrawal-induced anhedonia may be common to non-drug-induced anhedonia seen in MDD and schizophrenia. Thus, understanding the neural mechanisms of psychostimulant withdrawal-induced anhedonia will not only help to decrease the burden of psychostimulant dependence, but may also provide insights into other psychopathological states, such as depression and schizophrenia. Acknowledgments This work was supported by NIH research grants U01 MH69062, R01 DA11946 and R01 DA232090, and research grant 15RT-0022 from the Tobacco-Related Disease Research Program of the State of California. The authors wish to thank Mr. Michael Arends for outstanding editorial assistance and Ms. Janet Hightower for graphics.

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Sensitization Processes in Drug Addiction Louk J.M.J. Vanderschuren and R. Christopher Pierce

Contents 1 Incentive Sensitization: Basic Tenets and Observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 2 Sensitization of the Incentive Value of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 3 Sensitization After Extended Drug Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 4 Sensitization and Relapse to Drug Seeking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 5 Limitations of the Incentive-Sensitization View of Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 6 Sensitization in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

Abstract In 1993, Robinson and Berridge published their first review that laid out the incentive sensitization theory of addiction (Robinson and Berridge 1993 Brain Res Rev 18:247). Its basic point is that repeated exposure to drugs of abuse causes hypersensitivity to drugs and drug-associated stimuli of the neural circuits mediating incentive salience, an important way in which motivational stimuli influence behavior. In laymen’s terms, it states that this drug-induced hypersensitivity of motivational circuitry would mediate an increase in drug “wanting,” thus being responsible for the dramatically exaggerated motivation for drugs displayed by addicts. This theory has been exceptionally influential, as evidenced by the fact that the original review paper about this theory (Robinson and Berridge 1993 Brain Res Rev 18:247) has been cited 2,277 times so far, and subsequent updates of this view

L.J.M.J. Vanderschuren (*) Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands e-mail: [email protected] R.C. Pierce Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA


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(Robinson and Berridge 2000 Addiction 95(Suppl 2):S91; Robinson and Berridge 2001 Addiction 96:103; Robinson and Berridge 2003 Ann Rev Psychol 54:25) have been cited 274, 297, and 365 times, respectively, adding up to more than 3,200 citations within 15 years. The present chapter aims to delineate the merits and limitations of the incentive sensitization view of addiction, and whether incentive sensitization occurs in humans. We conclude that since incentive sensitization most prominently occurs after the first few drug exposures, it may represent an important initial step in the addiction process. During the expression of full-blown addiction, characterized by loss of control over drug intake and use of large quantities of drugs, the expression of incentive sensitization may be transiently suppressed. However, detoxification and the gradual disappearance of tolerance and withdrawal symptoms may unmask sensitization, which could then play an important role in the high risk of relapse. Keywords Incentive sensitization Reinforcement Motivation Self-administration Psychomotor activity

1 Incentive Sensitization: Basic Tenets and Observations One behavioral effect that many drugs of abuse have in common is that they evoke characteristic patterns of hyperactivity in laboratory animals (Wise and Bozarth 1987). Upon repeated exposure to drugs of abuse, particularly psychostimulants and opiates, there is a progressive and persistent increase in this drug-induced hyperactivity (Segal and Mandell 1974; Post and Rose 1976; Babbini and Davis 1972; Clarke and Kumar 1983). Interestingly, drug-induced enhancements in dopamine overflow in the nucleus accumbens (Di Chiara and Imperato 1988) have been intimately implicated in drug-induced hyperactivity, and sensitization of hyperactivity has been found to be associated with an increased capacity of drugs to enhance mesoaccumbens dopaminergic activity (Kalivas and Stewart 1991; Pierce and Kalivas 1997; Vanderschuren and Kalivas 2000). In addition, the mesoaccumbens dopamine projection is known to mediate motivational influences on behavior (not to be mistaken with subjective feelings of pleasure) (Berridge 2007; Salamone et al. 2005; Cardinal et al. 2002). Together, this fuelled the notion that repeated drug exposure causes brain motivational circuitry to become persistently hyperresponsive, or sensitized, to drugs and drug-associated stimuli. Sensitization of the mesoaccumbens dopamine system, which plays a prominent role in determining the manner that stimuli are perceived as desirable (Berridge and Robinson 1998; Berridge 2007), causes drugs and drug-associated stimuli to become excessively “wanted.” Importantly, according to the incentive-sensitization hypothesis, this exaggerated drug wanting can lead to the compulsive pursuit and consumption of the drug without sensitization of the drug’s subjective pleasurable effects (Robinson and Berridge 1993, 2008).

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2 Sensitization of the Incentive Value of Drugs An augmented psychomotor response to a drug challenge has long been considered a standard method to determine whether behavioral or incentive sensitization has occurred. However, at present, there seems to be a shift in the way of thinking about the standard readout of sensitization, as the increased motivation to self-administer drugs is clearly a more relevant way to address addiction-like behavior in animals. Moreover, although the neural substrates of drug-induced hyperactivity and its positive subjective properties overlap to a large extent (Wise and Bozarth 1987; Koob 1992; Pierce and Kumaresan 2006), measurement of locomotion is, at best, an indirect measure of a drug’s impact on reward and incentive motivational processes. Nonetheless, several important findings support the incentive sensitization view of addiction. For example, it has been repeatedly shown in two different but widely used models that nonvolitional drug treatment enhances the positive subjective and/ or reinforcing properties of drugs. Thus, repeated drug exposure enhances their capacity to evoke subsequent conditioned place preference, apparent as either lower drug doses or fewer conditioning trials being effective, or an increase in place preference magnitude (Lett 1989; Gaiardi et al. 1991; Shippenberg and Heidbreder 1995; Shippenberg et al. 1996; Meririnne et al. 2001; Manzanedo et al. 2005; Narita et al. 2004; Harris and Aston-Jones 2003a, b; Simpson and Riley 2005). Repeated drug pretreatment was also shown to enhance drug self-administration, apparent as either faster acquisition, acquisition at lower doses, or increased responding during early maintenance (Piazza et al. 1989, 1990; Horger et al. 1990, 1992; Valadez and Schenk 1994; Pierre and Vezina 1997, 1998; Covington and Miczek 2001). In addition, pretreatment with amphetamine also accelerated the escalation of cocaine self-administration, when animals were permitted long daily access to the drug (Ferrario and Robinson 2007). Even stronger evidence that preexposure to drugs enhances their motivational properties came initially from Philips and colleagues (Mendrek et al. 1998), findings that were subsequently replicated and extended by Vezina and colleagues and others (Lorrain et al. 2000; Covington and Miczek 2001; Suto et al. 2002, 2003; Vezina et al. 2002). These researchers showed that treating rats with amphetamine or cocaine according to a schedule that evokes sensitization to its psychomotor stimulant properties also caused these animals to work harder to receive amphetamine and cocaine under a progressive-ratio schedule that measures effort required for self-administration. This indicates that sensitized animals are more motivated to work for the drug. Importantly, not only experimenter-delivered drug pretreatment, but also a period of drug self-administration (as would happen in the real world, where drug exposure rarely occurs as passive treatment) has been shown to subsequently enhance its motivational properties. Thus, Roberts and colleagues have shown that a period of drug (cocaine or heroin) self-administration leads to increased break-points under a progressive ratio schedule of reinforcement (Liu et al. 2005b, 2007; Morgan et al. 2005, 2006; Ward et al. 2006). Remarkably, in these studies, sensitization of the incentive value of cocaine appeared to be most

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pronounced in animals with limited drug self-administration experience (Morgan et al. 2006). This is consistent with findings from psychomotor sensitization experiments, where sensitization can be induced by a single, or only a few drug exposures (Magos 1969; Robinson 1984; Robinson et al. 1982; Peris and Zahniser 1987; Kalivas and Alesdatter 1993; Vanderschuren et al. 1999a, 2001). Somewhat contrasting the findings from Roberts and colleagues, but consistent with findings from studies using extended access models of self-administration (discussed later), prolonged drug self-administration has been shown to increase the incentive value of the drug. Deroche et al. (1999) compared groups of rats with short (6 daily sessions) and long (29 daily sessions) cocaine self-administration experience, and found that certain motivational properties of the drug were augmented in the animals with the long cocaine taking history. The long-experience group showed a leftward shift in the dose–response curve for cocaine in an extinction–reinstatement paradigm, which assesses relapse to drug seeking after detoxification. In addition, the animals with long cocaine experience took less time to traverse a runway for cocaine reinforcement, suggesting that these animals were more motivated for the drug. Interestingly, cocaine-induced conditioned place preference did not differ between these groups, suggesting that not all positive motivational properties of the drug were enhanced (Deroche et al. 1999). Unfortunately, self-administration under a progressive ratio schedule was not tested in this study, precluding a direct comparison with the work of Roberts and colleagues. However, in a subsequent study from this group, break-points under a progressive ratio schedule for cocaine increased with prolonged cocaine self-administration experience, but this was only found in a subgroup of animals that also showed other characteristics of loss of control over drug use (Deroche-Gamonet et al. 2004).

3 Sensitization After Extended Drug Exposure Since drug addiction is usually the consequence of prolonged use of large quantities of drugs, there has been an increasing interest in recent years in animal models that emulate excessive drug intake. The most well-known of these is the so-called escalation model (Ahmed and Koob 1998). In this paradigm, animals are allowed to self-administer drugs for either brief or prolonged daily sessions. In the case of cocaine, this usually means 1 h vs. 6 h of access to cocaine. Animals that selfadminister cocaine for 6 h/day then display a gradual increase, or escalation, of drug intake, whereas cocaine intake in the animals that self-administer the drug for 1 h/day remains stable over time (Ahmed and Koob 1998). Clearly, if incentive sensitization underlies drug addiction, then animals with escalated cocaine intake would show behavioral changes associated with sensitization. When motivation to self-administer cocaine was assessed using a progressiveratio schedule of reinforcement, animals with a history of longer daily access to cocaine or heroin self-administration displayed increased breakpoints (Paterson


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and Markou 2003; Wee et al. 2008; Lenoir and Ahmed 2008; Orio et al. 2009). However, Roberts and colleagues did not find that escalation of cocaine intake is associated with increased motivation for the drug (Liu et al. 2005a), and one study actually showed that access to large quantities of the drug decreased the subsequent motivation to take cocaine (Morgan et al. 2006). A recent analysis from this same laboratory showed that escalation of cocaine intake increased the motivation for cocaine at high unit doses, but reduced the rate of responding at a threshold dose of cocaine (i.e., the lowest dose that reliably supports self-administration) (Oleson and Roberts 2009). These data suggest that animals with a history of escalated cocaine intake consume more of the drug if large amounts are available, but are not willing to pay a high price for a low amount of the drug (Oleson and Roberts 2009). In contrast, escalation of heroin self-administration was shown to increase the value of the drug, as the maximum price animals were willing to pay for heroin (number of responses/reinforcer, as well as response rate) was increased (Lenoir and Ahmed 2008). Together, these data show that a history of escalated drug intake may indeed increase the incentive motivational value of the drug, possibly depending on a number of experimental variables. However, animals with escalated drug intake fail to show two other indices of behavioral sensitization, including increased behavioral activation and nucleus accumbens dopamine in response to a challenge injection of the drug. Thus, after escalated cocaine or heroin self-administration, no psychomotor sensitization was found (Ben-Shahar et al. 2004, 2005; Ahmed and Cador 2006; Lenoir and Ahmed 2007; Ferrario et al. 2005; Knackstedt and Kalivas 2007). These data suggest that increased responsiveness to the psychomotor effects and increased motivation for the drug are not necessarily a manifestation of the same neurobehavioral process (see also Lack et al. 2008). One study found that stereotyped head movements rather than psychomotor activity were sensitized after cocaine treatment in animals that had self-administered cocaine in long-access sessions (Ferrario et al. 2005; but see Knackstedt and Kalivas 2007). Since the effect of psychomotor stimulant drugs on stereotyped behavior depends on dorsal rather than ventral striatal dopamine (Joyce and Iversen 1984; Kelly et al. 1975), this suggests that escalated animals would show increased dopaminergic responsiveness in dorsal, but not ventral striatum. Indeed, animals with a history of escalated cocaine self-administration do not show hyperdopaminergic responses to the drug in the nucleus accumbens, in terms of increased dopamine concentrations after cocaine (Ahmed et al. 2003). In fact, dopamine reactivity in the nucleus accumbens to cocaine has even been shown to be dramatically decreased after excessive cocaine self-administration (Mateo et al. 2005). In view of the sensitized stereotypy observed after escalated cocaine self-administration, it would therefore be of interest to investigate dopaminergic reactivity to the drug in dorsal striatum after escalated cocaine self-administration. Taken together, prolonged or excessive drug self-administration can result in exaggerated motivation for drugs, but whether this is the result of a neural and behavioral sensitization process is unclear, because two hallmark features of behavioral sensitization are absent following excessive drug self-administration.

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Thus, augmented psychomotor stimulant effects of drugs and an increased dopamine overflow in nucleus accumbens are absent, the latter of which should mediate the excessive salience of drugs and drug-associated cues. While cocaine selfadministration under progressive ratio schedules may reflect motivation for the drug, it has been suggested that the upward shift in the dose–response curve for cocaine under this schedule in escalated animals (Paterson and Markou 2003; Wee et al. 2008; Lenoir and Ahmed 2008) signifies a downregulation of brain reward processes. Thus, if animals are more motivated to work for any unit dose of cocaine, this suggests that they need more drug to achieve the desired positive effect (Ahmed 2005; Lenoir and Ahmed 2008, but see Oleson and Roberts 2009). On the other hand, the leftward shift in the dose–response curve for amphetamine seen in sensitized animals (Vezina et al. 2002) may rather indicate enhanced motivation for the drug, since animals only work harder for low unit doses. This issue clearly warrants further investigation.

4 Sensitization and Relapse to Drug Seeking The long-lasting character of sensitization suggests that sensitization plays a role in persistent aspects of addiction, besides a long-lasting increase in the motivation for drugs. Perhaps the most important persistent aspect of addiction is the risk of relapse to drug abuse, which can remain present for years or even decades after detoxification. Relapse to drug seeking after detoxification is widely investigated using the extinction–reinstatement model (Shaham et al. 2003). In this paradigm, drug self-administration is acquired by animals and subsequently extinguished by no longer reinforcing operant behavior with drug delivery. The critical test is the reinstatement of operant behavior, which can be achieved by drug priming (usually the same drug that was initially self-administered), response-contingent presentation of drug-associated cues, or stress. Since operant behavior is not reinforced during this phase of the experiment, it is interpreted as reflecting drug seeking rather than drug taking. Using a pharmacological approach, it was shown that dopaminergic and opioid drugs that evoked sensitized psychomotor responses also reinstated drug seeking after extinction (De Vries et al. 1998, 1999, 2002; Vanderschuren et al. 1997; 1999b, c; Dias et al. 2004). Interestingly, there was considerable overlap between the drugs that reinstated cocaine seeking and heroin seeking, but the pharmacological profile of relapse to psychostimulant and opiate seeking was not identical, suggesting that the neural substrates of relapse to drug seeking are to a certain extent drug-specific. Additional evidence for a positive relation between psychomotor sensitization and reinstatement of drug seeking comes from the observation that AMPA receptor stimulation in the nucleus accumbens is important for both processes (Bell and Kalivas 1996; Cornish et al. 1999; Pierce et al. 1996; Park et al. 2002; Famous et al. 2008; Ping et al. 2008; Conrad et al. 2008). Furthermore, rats pretreated with amphetamine and subsequently trained to selfadminister cocaine were more motivated to work for the drug under a progressive


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ratio schedule of self-administration (Suto et al. 2003), and were also more sensitive to the reinstating effect of intra-accumbens treatment with AMPA (Suto et al. 2004). Further evidence for the involvement of nucleus accumbens AMPA receptor stimulation in both reinstatement of cocaine seeking and expression of sensitization to the psychomotor stimulant effect of cocaine was shown in a recent study that manipulated expression of the AMPA receptor subunit GluR1 in the accumbens. This study found that overexpression of GluR1 reduced sensitization and reinstatement, whereas downregulation of GluR1 enhanced both processes (Bachtell et al. 2008). However, as mentioned above, animals showing escalated cocaine or heroin intake show no psychomotor sensitization, but they do display an increased sensitivity to the ability of the drug to reinstate extinguished drug seeking (Ben-Shahar et al. 2004, 2005; Ahmed and Cador 2006; Lenoir and Ahmed 2007; Ferrario et al. 2005; Mantsch et al. 2004; Knackstedt and Kalivas 2007). Furthermore, some studies have not found a relationship between the ability of drugs to evoke a sensitized psychomotor response and to reinstate drug seeking (Sutton et al. 2000). Together, these data suggest that part of the neural changes underlying psychomotor sensitization also play a role in relapse to drug seeking even if these are two different manifestations of behavior, but also that the mechanisms involved are not identical and may even differ between animals with different drug taking histories.

5 Limitations of the Incentive-Sensitization View of Addiction Although repeated drug exposure can enhance the incentive value of drugs, there are two lines of evidence that argue against the notion that incentive sensitization can fully explain drug addiction. First, by and large, a few drug exposures usually suffice to induce psychomotor sensitization. In fact, even a single drug exposure can induce long-lasting behavioral sensitization and associated neural changes (Magos 1969; Robinson 1984; Robinson et al. 1982; Peris and Zahniser 1987; Kalivas and Alesdatter 1993; Vanderschuren et al. 1999a, 2001). However, before full-blown drug addiction develops, people have usually taken large quantities of drugs over prolonged periods of time. Thus, casual drug use may not be without lasting consequences, and the incentive sensitization evoked by limited drug exposure may be an important first step in the addiction process, but sensitized individuals are not necessarily addicted. Second, repeated pretreatment with drugs increases the incentive value of drugs, but also of nondrug reinforcers. Thus, drug pretreatment facilitates sexual behavior (Fiorino and Phillips 1999a, 1999b), approach behavior to sexual stimuli and palatable food (Nocjar and Panksepp 2002, 2007), as well as lever pressing for food (Nordquist et al. 2007; Olausson et al. 2006). Interestingly, amphetamine-pretreated rats do not consume more sucrose when it is freely available (Nordquist et al. 2007), suggesting that it is the motivation for food (“wanting”) rather than its hedonic value (“liking”) that is increased in amphetaminesensitized rats (Robinson and Berridge 1993). In addition, drug pretreatment has

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been shown to enhance the impact of food-associated stimuli on behavior in paradigms measuring conditioned approach, responding for conditioned reinforcement, and Pavlovian-to-instrumental transfer (Harmer and Phillips 1998; Taylor and Jentsch 2001; Taylor and Horger 1999; Mead et al. 2004; Olausson et al. 2004; Wyvell and Berridge 2001). Importantly, animals pretreated with amphetamine displayed not only enhanced acquisition of conditioned approach, but also accelerated acquisition of conditioned inhibition (Harmer and Phillips 1999). This excludes the possibility that the increases in conditioned responding for food are solely the result of increased locomotor activity in sensitized animals. Together, these data show that in animals showing psychomotor sensitization, the motivation for nondrug reinforcers, as well as the ability of stimuli associated with them to gain control over behavior, is augmented. Thus, repeated drug exposure appears to evoke a generalized enhancement in the responsiveness of the neural systems involved in motivation, rather than specific increases in the motivation for artificial (i.e., drug) reinforcers. Indeed, sensitization of the psychomotor stimulant properties of cocaine does not appear to alter the relative preference of animals for highly palatable sweet solutions over the drug (Lenoir et al. 2007). Together, these observations in sensitized animals are inconsistent with one of the core symptoms of addiction as formulated in DSM IV (American Psychiatric Association 2000); i.e., the sacrifice or disinterest in natural reinforcement such as social and professional activities in favor of drug-related activities.

6 Sensitization in Humans An important question regarding incentive sensitization that has eluded researchers is whether it occurs among human drug addicts. One practical explanation for the lack of evidence is that ethical reasons prohibit sensitization experiments in humans in the same way as they are usually performed in animals. Thus, experiments that compare the responsivity to drugs in drug-experienced vs. drug-naı¨ve individuals have not been widely performed, nor have many studies assessed the gradual change in drug effects during the first few drug exposures. Of the relatively few studies that have examined whether sensitization of behavioral or neurochemical effects of drugs occurs in humans, the most clear-cut data come from studies in drug-naı¨ve individuals. Thus, studies from Strakowski and colleagues (Strakowski et al. 1996, 2001; Strakowski and Sax 1998) have shown that effects of amphetamine on parameters such as activity, energy, elevated mood, euphoria, speech, and eye-blink rate are increased in subjects that receive amphetamine for the second or third time, as compared to the first amphetamine exposure. Interestingly, effects of amphetamine on “drug liking” were actually highest after the first (compared to third) amphetamine treatment (Strakowski et al. 2001). A recent comprehensive study on the behavioral and neurochemical effects of amphetamine for up to 1 year after the first amphetamine treatment also demonstrated the occurrence of sensitization (Boileau et al. 2006). In this study,


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drug-naı¨ve volunteers were treated with amphetamine three times over 5 days, and then again 14 days and 1 year later. As compared to the first amphetamine dose, the effects on agreeableness and clearheadedness were largest at the 14-day follow-up, and the effects on energy were elevated at the 14-day, as well as the one-year follow-up. In addition, effects on dopamine release were increased in both dorsal and ventral striatum at both follow-up times as measured by positron emission tomography (PET) scans of dopamine D2 receptor displacement (Boileau et al. 2006). Thus, as found in rodents, sensitization in humans can be observed in drug-naı¨ve individuals after repeated amphetamine treatment. However, these studies contrast with negative findings on the sensitization of behavior and striatal dopamine release effects of amphetamine when comparing the second to first amphetamine exposure in drug-naı¨ve individuals (Wachtel and De Wit 1999; Kegeles et al. 1999). As would be expected from animal studies, sensitizing behavioral effects of amphetamine and cocaine have not been observed in humans with a history of psychostimulant abuse, even if they had never developed addiction and were drug-free at the time of the experiment (Kelly et al. 1991; Johanson and Uhlenhuth 1981; Rothman et al. 1994), although one study found sensitization of cardiovascular (but not subjective) effects of cocaine in former addicts (Kollins and Rush 2002). These findings are consistent with the notion that sensitization occurs during initial drug exposures, and once sensitization has occurred, it is long-lasting but no further sensitization can be induced due to a ceiling effect. One form of psychostimulant sensitization that is often observed in human addicts is the occurrence of paranoid psychosis. Interestingly, psychosis can be re-evoked or exacerbated in abstinent individuals with doses of drugs that are lower than the ones that were initially used when psychosis developed (Sato et al. 1983), comparable with the expression of sensitized psychomotor activity in rodents. The relationship between psychosis and psychostimulant addiction is not clear, as both positive and negative correlations between psychosis and cocaine craving have been reported (Reid et al. 2004; Bartlett et al. 1997). The question remains whether behavioral and neurochemical sensitization can be observed in human addicts. As far as we know, no pertinent study has as yet addressed the issue of whether the behavioral effects of drugs are sensitized in addicts, although the high motivation to obtain drugs that characterizes addiction can in itself be taken as evidence for incentive sensitization. However, in contrast to drug-naı¨ve individuals, studies on dopaminergic sensitization in human addicts have yielded negative evidence. In humans addicted to alcohol or cocaine, challenges with amphetamine or methylphenidate resulted in reduced dopamine release in the striatum compared to controls as assessed using PET scan of dopamine D2 receptor binding (Martinez et al. 2005, 2007; Volkow et al. 1997), opposite to increases that would be expected from a sensitization hypothesis. Interestingly, cocaine-dependent subjects also reported a reduced “high” after methylphenidate, suggesting reduced drug “liking” (Volkow et al. 1997).

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7 Conclusions Sensitization to the psychomotor activating effects of drugs of abuse can be readily observed after repeated drug treatment, and psychomotor sensitization is an effect that drugs of abuse probably have in common. This behavioral change is usually associated with hyperresponsiveness of the mesoaccumbens dopamine projection (Robinson and Berridge 1993; Pierce and Kalivas 1997; Vanderschuren and Kalivas 2000). Since this pathway mediates motivational influences on behavior (Berridge 2007; Salamone et al. 2005; Cardinal et al. 2002), its heightened sensitivity has been hypothesized to underlie the excessive motivation for drugs in addicts (Robinson and Berridge 1993). The available data suggest an involvement of sensitization in certain, but not all, phases and aspects of drug addiction. In rodents, primates (Bradberry 2007) and humans (discussed earlier), psychomotor and dopaminergic sensitization is quite consistently found after limited drug experience; it develops quickly after the first few drug exposures in otherwise drugnaive individuals. This sensitization is associated with enhanced rewarding and reinforcing effects of drugs. However, after excessive drug intake, there is neither sensitization of the psychomotor effects of drugs nor sensitization of the nucleus accumbens dopamine response, even if enhanced motivation for the drug persists. This suggests that psychomotor sensitization does not play a major role in the genuine expression of addictive behavior. Indeed, animal studies aimed at emulating addiction-like behavior in rats have found that enhanced motivation for cocaine either is not apparent during loss of control over drug intake (Vanderschuren and Everitt 2004), or precedes the development of this effect (Deroche-Gamonet et al. 2004). Together with findings that sensitized animals show increased motivation for natural reinforcers, this suggests that incentive sensitization represents a generalized increase in the sensitivity of neural systems that regulate motivated behavior. We, therefore, think that incentive sensitization is an important initial step in the addiction process, whereby the first few occasions of drug use enhance the attractiveness of drugs and promote further use. During these drug use episodes, the association of environmental stimuli with drug effects will be readily made, and these drug-associated cues would quickly gain control over behavior (Everitt and Robbins 2005). The combination of these phenomena would greatly enhance the likelihood of further drug use, which may then escalate into large quantities of drug intake with prolonged use, culminating in the loss of control over drug intake that characterizes addiction. During this latter phase of the addiction process, sensitization is masked by other behavioral and neural changes such as a reduced sensitivity of brain reward pathways (Koob et al. 2004). However, this does not mean that the neural changes underlying sensitization have been reversed. In fact, animal studies have shown that sensitization can be extremely long-lasting (e.g., Paulson et al. 1991), and is most prominently observed after a drug-free period (Pierce and Kalivas 1997; Vanderschuren and Kalivas 2000). Thus, after detoxification, sensitization could re-emerge to play a role in some of the more persistent aspects of addiction, such as the high risk for relapse that can remain for a lifetime.


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Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20 Shippenberg TS, Heidbreder C (1995) Sensitization to the conditioned rewarding effects of cocaine: pharmacological and temporal characteristics. J Pharmacol Exp Ther 273:808–815 Shippenberg TS, Heidbreder Ch, Lefevour A (1996) Sensitization to the conditioned rewarding effects of morphine: pharmacology and temporal characteristics. Eur J Pharmacol 299:33–39 Simpson GR, Riley AL (2005) Morphine preexposure facilitates morphine place preference and attenuates morphine taste aversion. Pharmacol Biochem Behav 80:471–479 Strakowski SM, Sax KW (1998) Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans. Biol Psychiatry 44:1171–1177 Strakowski SM, Sax KW, Setters MJ, Keck PE (1996) Enhanced response to repeated d-amphetamine challenge: evidence for behavioral sensitization in humans. Biol Psychiatry 40:872–880 Strakowski SM, Sax KW, Rosenberg HL, DelBello MP, Adler CM (2001) Human response to repeated low-dose d-amphetamine: Evidence for behavioral enhancement and tolerance. Neuropsychopharmacology 25:548–554 Suto N, Austin JD, Tanabe LM, Kramer MK, Wright DA, Vezina P (2002) Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in a D1 dopamine receptor dependent manner. Neuropsychopharmacology 27:970–979 Suto N, Tanabe L, Austin JD, Creekmore E, Vezina P (2003) Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in an NMDA, AMPA/kainate, and metabotropic glutamate receptor-dependent manner. Neuropsychopharmacology 28:629–639 Suto N, Tanabe LM, Austin JD, Creekmore E, Pham CT, Vezina P (2004) Previous exposure to psychostimulants enhances the reinstatement of cocaine seeking by nucleus accumbens AMPA. Neuropsychopharmacology 29:2149–2159 Sutton MA, Karanian DA, Self DW (2000) Factors that determine a propensity for cocaineseeking behavior during abstinence in rats. Neuropsychopharmacology 22:626–641 Taylor JR, Horger BA (1999) Enhanced responding for conditioned reward produced by intraaccumbens amphetamine is potentiated after cocaine sensitization. Psychopharmacology 142:31–40 Taylor JR, Jentsch JD (2001) Repeated intermittent administration of psychomotor stimulant drugs alters the acquisition of pavlovian approach behavior in rats: Differential effects of cocaine, d-amphetamine and 3, 4-methylenedioxymethamphetamine (“ecstasy”). Biol Psychiatry 50:137–143 Valadez A, Schenk S (1994) Persistence of the ability of amphetamine preexposure to facilitate acquisition of cocaine self-administration. Pharmacol Biochem Behav 47:203–205 Vanderschuren LJMJ, Everitt BJ (2004) Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305:1017–1019 Vanderschuren LJMJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120 Vanderschuren LJMJ, Tjon GHK, Nestby P, Mulder AH, Schoffelmeer ANM, De Vries TJ (1997) Morphine-induced long term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen. Psychopharmacology 131:115–122 Vanderschuren LJMJ, Schmidt ED, De Vries TJ, Van Moorsel CAP, Tilders FJH, Schoffelmeer ANM (1999a) A single exposure to amphetamine is sufficient to induce long-term behavioral, neuroendocrine and neurochemical sensitization in rats. J Neurosci 19:9579–9586 Vanderschuren LJMJ, Schoffelmeer ANM, Mulder AH, De Vries TJ (1999b) Dopaminergic mechanisms mediating the long-term expression of locomotor sensitization following preexposure to morphine or amphetamine. Psychopharmacology 143:244–253


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Imaging Receptor Changes in Human Drug Abusers Kelly P. Cosgrove

Contents 1 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Cocaine and the Dopamine Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Cocaine and the D2/3 Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Cocaine and the Serotonin Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Cocaine and the mu-Opioid Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Alcohol and the D2/3 Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Alcohol and the Dopamine Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Alcohol and the Serotonin Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Alcohol and the mu-Opioid Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Alcohol and the GABAA-BZ Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Nicotine and the b2-Nicotinic Acetylcholine Receptor (b2*-nAChR) . . . . . . . . . . . . . . 4.2 Nicotine and the D1 Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Nicotine and the D2/3 Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Nicotine and the Dopamine Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Nicotine and the Serotonin Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Opiates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Opiate Dependence and the mu-Opioid Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Opiate Dependence and the D2/3 Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

200 201 201 202 203 203 204 204 205 206 207 208 209 209 210 210 211 211 211 211 212 212 213

Abstract This chapter will review the literature on differences in the brain chemistry of alcohol- and drug-dependent individuals compared to healthy controls as measured with positron emission tomography and single photon emission computed tomography. Specifically, alterations in dopamine, serotonin, opioid, and K.P. Cosgrove Department of Psychiatry 116A6, Yale University School of Medicine and the VACHS, 950 Campbell Avenue, West Haven, CT 06516, USA e-mail: [email protected]


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GABA systems in cocaine, alcohol, nicotine, and heroin dependence have been examined. These neurochemical systems are integrated and play significant roles in a final common pathway mediating addiction in the brain. One recurrent finding is that dopaminergic dysfunction is prevalent in both alcohol and drug dependent populations, and specifically there is a lower availability of dopamine type 2/3 receptors in cocaine-, alcohol-, nicotine-, and heroin-dependent individuals compared to healthy controls. The development of novel radiotracers that target additional receptor systems will further our understanding of the neurochemical basis of addiction. Keywords Imaging PET SPECT Drug abuse Alcohol Cocaine Nicotine

Abbreviations PET SPECT DA 5-HT GABAA-BZR b2*-nAChR D1 D2/3

Positron emission tomography Single Photon emission computed tomography Dopamine Serotonin GABAA-benzodiazepine receptor b2*-subtype of the nicotinic acetylcholine receptor Dopamine type 1 receptor Dopamine type 2/3 receptor

1 Introduction This chapter will briefly review the literature on differences in the brain chemistry of individuals with alcohol and drug dependence versus healthy, nondependent individuals in vivo as measured with positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging. Importantly, in humans we are not able to obtain “baseline” scans on drug dependent individuals from when they were drug-naı¨ve; thus, data collected in drug abusers are typically compared to age-matched healthy controls. This means that we do not know whether the brain changes are pre-existing and represent a vulnerability to addiction, or whether they are a consequence to drug use. PET and SPECT receptor imaging is typically used to examine the neurochemistry of addiction during early detoxification and also during longer periods of withdrawal. The length of abstinence is an important variable to take into account in imaging studies, because different receptor systems have been shown to change during the recovery from drug and alcohol dependence, some in as little as several weeks; thus, length of

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abstinence will be noted when it is available. We cannot currently determine in humans whether differences in receptor or transporter availability are pre-existing or are a consequence; thus, this alternative conclusion is a caveat in all sections of this chapter. It is also important to note that many individuals with drug addiction also drink alcohol and/or smoke cigarettes, making it a complex process to determine which variable or combination of variables are contributing to the receptor changes. In the majority of studies, to date, smoking is not systematically controlled; thus, additional research will be required to untangle these relationships. PET and SPECT may also be used to measure striatal dopamine (DA) transmission, e.g., drug-induced changes in DA release, and this is covered in another chapter by Dr. Martinez. We refer to receptor “availability” as opposed to receptor “levels” or “density” throughout the chapter to note that these studies are measuring receptors that are available to be bound by the radiotracer. This is because the radiotracer cannot bind to receptors that are already occupied, perhaps by the drug; e.g., cocaine, or an endogenous neurotransmitter such as dopamine. We are currently able to image a limited number of receptor systems in the brain; thus, the scope of this review is limited to existing radiotracers that are currently approved for use in humans.

2 Cocaine 2.1

Cocaine and the Dopamine Transporter

Cocaine acts directly at the DA transporter by blocking the reuptake of dopamine. Several studies report higher striatal DA transporter availability in acutely abstinent cocaine-dependent subjects compared to healthy controls using [123I]beta-CIT SPECT (Jacobsen et al. 2000; Malison et al. 1998). Additionally, higher DA transporter availability was associated with worse scores on the Hamilton depression inventory (Malison et al. 1998). However, no difference in striatal DA transporter availability between chronic cocaine abusers (last use of cocaine was 5 8 days) versus controls, but lower striatal DA transporter availability in detoxified cocaine abusers (last use 42 7 days) was reported using [11C]cocaine PET (Wang et al. 1997a). Differences in these studies are likely due to differences between the radiotracers [123I]beta-CIT and [11C]cocaine. Specifically, [11C]cocaine is limited due to its low specific to nonspecific binding ratio and rapid clearance, and thus is more of a blood flow agent. It is also important to note that we do not know the halflife of cocaine in the brain; thus, while it rapidly clears in the blood it may remain in the brain for a longer period of time and interfere with radiotracer binding. A recent study using [99mTc]TRODAT, which labels striatal DA transporters, and SPECT also reported higher striatal DA transporter availability in recently abstinent (7.5 9.7 days) cocaine dependent subjects vs. controls (Crits-Christoph et al. 2008). And, DA transporter levels tended to decrease with days since last use, suggesting that cocaine-induced increases in DA transporter availability may

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decrease during more prolonged abstinence. Because cocaine acts by blocking the reuptake of dopamine at the DA transporter, an increase in DA transporter availability suggests that chronic cocaine use induces a compensatory upregulation of the DA transporter. This is further supported by the data suggesting that when cocaine is removed, e.g., during prolonged abstinence, DA transporter availability decreases.

2.2

Cocaine and the D2/3 Receptor

There is a transient increase in DA levels in brain when cocaine blocks the DA transporter. The increase in DA levels is critical to cocaine’s reinforcing effects, and thus cocaine-induced changes in DA receptor levels have been the subject of many studies (Table 1). For example, recently detoxified (within 1 week) cocaine abusers had lower striatal dopamine type 2/3 (D2/3) receptor availability measured with [18F]N-methylspiroperidol PET (Volkow et al. 1990) compared to healthy controls. In the same study, cocaine abusers (n ¼ 3) with 1 month of abstinence had similar striatal D2/3 receptor availability compared to controls (Volkow et al. 1990). A subsequent study, also using [18F]N-methylspiroperidol PET, in a larger sample of cocaine abusers (n ¼ 20) demonstrated lower striatal D2/3 receptor availability at 1 and 4 months of abstinence compared to healthy controls (Volkow et al. 1993), suggesting that the initial decrease in D2/3 receptor availability persists. These findings were further replicated using [11C]raclopride PET. Specifically, chronic cocaine abusers had lower striatal D2/3 receptor availability during withdrawal, at approximately 2 weeks of abstinence (Martinez et al. 2004) and at 3–6 weeks of abstinence compared to healthy controls (Volkow et al. 1997). Taken together, these studies suggest that the striatal dopamine system compensates for chronic cocaine use by decreasing the number of postsynaptic D2/3 receptors, and this decreased availability persists with prolonged abstinence. The ultimate effect in a chronic cocaine abuser is a dysregulated DA system which has important treatment implications; e.g., these individuals may be more resistant to treatment drugs that target DA neurotransmission. There does not appear to be a correlation between availability of D2/3 receptors and the reinforcing effects of cocaine in cocaine addiction. While high versus low striatal D2/3 receptor availability predicts Table 1 Studies examining D2/3 receptor availability in cocaine dependence compared to controls Radiotracer Time abstinent Main finding Reference 1 week Lower availability Volkow et al. (1990) [18F]N-methylspiroperidol 1 month Similar availability Volkow et al. (1990) [18F]N-methylspiroperidol 1 and 4 months Lower availability Volkow et al. (1993) [18F]N-methylspiroperidol 2 weeks Lower availability Martinez et al. (2004) [11C]raclopride 3–6 weeks Lower availability Volkow et al. (1997) [11C]raclopride 11 C and 18F radioisotopes are used with PET

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unpleasant versus pleasurable experiences, respectively, to stimulants in healthy controls (Volkow et al. 1999, 2002a); this correlation was not replicated in cocainedependent individuals (Martinez et al. 2004). Lower D2/3 receptor availability in dependent individuals compared to healthy controls has emerged as a consistent marker across all addictions. An alternative conclusion may be that addicted individuals have decreased D2/3 receptor availability prior to any drug use and that this represents vulnerability rather than consequence.

2.3

Cocaine and the Serotonin Transporter

While much of the work on the reinforcing and withdrawal effects of cocaine has focused on DA neurotransmission, serotonin (5-HT) dysfunction may also be involved since cocaine exhibits high affinity for the 5-HT transporter and increases 5-HT reuptake, which likely contributes to changes in mood associated with cocaine. Specifically, dopamine may be more involved in the locomotor activating effects and euphoric effects of cocaine, while serotonin may be important in the worsening mood that is reported during cocaine withdrawal. We can measure the 5-HT transporter in the diencephalon and brainstem with [123I]beta-CIT and SPECT. Using this paradigm, Jacobsen et al. (2000) reported higher diencephalon and brainstem 5-HT transporter availability in smoked cocaine-dependent subjects during acute abstinence (e.g., 3.7 3.8 days) compared to healthy controls. Higher 5-HT transporter availability is likely a compensatory upregulation to chronic cocaine use. Because the transporters remove extracellular serotonin, increased transporter availability may result in a decrease in synaptic serotonin levels, which may influence mood during acute withdrawal from cocaine. However, no correlations between transporter availability and measures of mood, impulsivity, or aggression were found (Jacobsen et al. 2000). Additional studies are needed to determine whether chronic cocaine use leads to changes in 5-HT transporters over more prolonged abstinence.

2.4

Cocaine and the mu-Opioid Receptor

The opioid system is widely implicated in the reinforcing effects of most drugs of abuse including cocaine. There are three opioid receptors (mu, delta, kappa) that are typically studied, and the mu-opioid receptor is known for modulating the positive reinforcing effects of drugs of abuse. [11C]carfentanil PET has been used to measure mu-opioid receptor availability. In cocaine addicts during acute withdrawal (1–4 days), mu-opioid receptor availability was higher in the frontal and temporal cortices and anterior cingulate compared to healthy controls, and was positively correlated with the severity of craving on the day of the scan (Gorelick

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et al. 2005; Zubieta et al. 1996). Additionally, mu-opioid receptor availability increases over the first week of abstinence, remains elevated up to 4 weeks of abstinence, and begins to decrease to control levels by 12 weeks of abstinence (Gorelick et al. 2005; Zubieta et al. 1996). A recent study examined the relationship between mu-opioid receptor availability and time to relapse in cocaine users (Gorelick et al. 2008). Specifically, higher mu-opioid receptor availability at 1 and 12 weeks of abstinence in the frontal and temporal cortices was significantly associated with a shorter time to relapse. Put another way, the greater the decline in mu-opioid receptor availability during a 12-week abstinence period, the longer the time to relapse after discharge. These studies suggest that the mu-opioid receptor plays a critical role in craving and relapse in cocaine users and may direct pharmacotherapies during abstinence and/or may provide a biochemical marker that helps identify individuals at high-risk of early relapse.

3 Alcohol 3.1

Alcohol and the D2/3 Receptor

Alcohol’s rewarding effects are largely linked to the mesolimbic dopamine system (Vengeliene et al. 2008), and specifically, the D2/3 receptor plays a role in mediating the reinforcing effects of alcohol. As mentioned previously, [11C]raclopride is widely used to examine the availability of D2/3 receptors. Here, the studies examining D2/3 receptor availability used [11C]raclopride unless otherwise noted. Initial studies in this area indicated lower striatal D2/3 receptor availability in alcohol dependent subjects compared to controls (Hietala et al. 1994; Volkow et al. 1996a). Two additional studies by Dr. Heinz and colleagues found lower D2/3 receptor availability with [18F]desmethoxyfallypride PET in alcoholdependent subjects compared to controls (Heinz et al. 2004b, 2005b). And, two SPECT studies reported nonsignificantly lower D2/3 receptor availability in alcohol-dependent subjects compared to controls (Guardia et al. 2000; Repo et al. 1999). While many studies examine alcohol-dependence as a heterogeneous population, there is some evidence to subgroup alcohol dependence, specifically into Cloninger’s Type I and II subtypes (Cloninger et al. 1988). Type I alcoholics are described as displaying a late-onset of alcoholism, (>25 years old), and they are initially more affected by the antianxiety effects of alcohol. Type II alcoholics typically have an early-onset of alcoholism (

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