No title

INTERNATIONAL REVIEW OF

Neurobiology VOLUME 8

Contributors To This Volume Denise Albe-Fessard Raymond A. Beck David Bowsher GL'nter G. Brune Leonide Goldstein Paul A. J. Janrsen James 1. McGaugh Lewis F. Petrinovich

Ch. Stumpf Lowell E. White, Jr.

INTERNATIONAL REVIEW OF

Neurobioloav Edited by CARL C . PFEIFFER New jersey Psychiafric Institute Princefon, New Jersey

JOHN R. SMYTHIES Department of Psychological Medicine University of Edinburgh, Edinburgh, Scotland

Associate Editors W. R. Adey

Sir John Eccles

C. Hebb

V. Amassian

E. V. Evarts

K. Killam

D. Bovet

H. J. Eysenck

S. M:rtens

Sir Russell Brain

G. W. Harris

0. Zangwill

J. M. R. Delgado

R. G. Heath

VOLUME

8 1965

@ ACADEMIC PRESS

New York and London

COPYRIGHT

0 1965,

BY

ACADEMIC PRESS

INC.

ALL RIGHTS RESERVED. NO PART OF THIS BOOK MAY BE REI’ROUUCED IN ANY F O R M ,

BY PHOTOSTAT, MICROFILhI, OR ANY OTHER MEANS, WITHOUT WRITTEN I’ERMISSION

1WOM THE PUBLISHERS.

ACADEMIC PRESS INC. 111 Fifth A v e n u e , New York, New York 10003

United Kingdom Edition published by ACADEMIC PRESS I N C . (LONDON) LTD Berkeley Squartb House, London W . l

LIBRARYOF

CONCRESS CATALOG C A R D NUMBER:

PRINTED IN THE UNITED STATES OF AMERICA

59-13822

To

F. Georgi

This Page Intentionally Left Blank

CONTR IBUTORS Numbers in parentheses indicate the pages on which the authors' contributions begin.

DENISEALBE-FESSARD (35), Faculty of Science, Laboratoire de Ph ysiologie des Centres Nervezix, Paris, France

RAYMONDA. BECK(265), Section on Neurophurmacology, Bureau of Research i n Neurology and Psychiatry, N e w Jersey Neuropsychiatric Institute, Princeton, N e w Jersey

DAVD BOWSHEH (35), Department of Anatomy, University of Liverpool, Liverpool, England, a i d Centre KEtudes de Physiologic Nerveusc, Uniuersity of Paris, Paris, France GUNTER G. BRUNE( 197), Neurologisclie Universitatsklinik und -Poliklinik, Hamburg, Gcrmany

LEON~DE GOLDSTEIN ( 265), Section on Neuropharmacology, Bureau of Research i n Neurology and Ps!ychimtry, N e w Jersey Neuropsychiatric Institute, Princcton, N m . Jersey

PAUL,4.J. JANSSEN (221), J a n s . ~ mPhnrmaceiitica, Research Laboratorin, Reerse, Belgium L. MCGAUGH(139), Department of Psychobiology, University of California, Irvine, California

JAMES

LEWISF. PETRINOVICH ( 139), Department of Psychology, State University of Nero York, Stony Brook, Long Island, N e w York

CH. STUMPF( 77), Department of Pharmacology, Emory University, Atlanta, Georgia, and lnstitute of Pharmacology, University of Vienna, Vienna, Austria

LOWELLE. WHITE,JR. ( l ) ,Division of Neurosurgery, University of Washington School of Medicine, Seattle, Washington vii

This Page Intentionally Left Blank

PREFACE Thc. major aim of this rcLvic.\v is t o provide a foriini in which the latest progress in the many inajor and diff erent sciences that make up neiirobiology can lie presentc,d for the edification not only of scientists working iii the sainr. science but also of thosc working in other disciplines. The usual order for the classificatiotr of knowlt,dge in medical science is iisccl in this volumc, iianiely a progression from anatomy and histology through chemistry and physiology to the clinical application of anatomical, physiolo~ical, pharmacological, and ps>.chological kno\vlcdge. This r t y ents thc orderly progression which will ultimately determine suc'oc:iinpal neurons ( Donier and Longo, 1962). Unfortunately, tlrcre arc no experimental data availa l ~ l eon the action of 5-HTP on tlw discharge pattern of septa1 ncwrons, \\hich would a l l o ~ a coiic1iision to lie drawn a s to \vlictl~er the disappearance of the theta rliytlnn under 5-HTP is due to an action similar to that producing the disappearance of this activity iindc>r LSD.

b. Action of 5-HTY on Hi])))ouiut)i(i/Actirjity after Infracrrrotid Iiijcctiori. Costa ct d.( 1960) foiintl that in rabbits intracarotid injection of 22 or 44 nig 5-HTY c~ius(’sa bipliasic E E G pattern in that a neocortical synchronizatioii is lollowed 11y desynclironizatioii. During the first stage an irregrilar activity and, during the, second stage, a theta rliythm \wre foiiiitl in the, liippoc:~nipus. It was suggested that 5-HTP acts directly i i p o i i some region of the reticular formation. A positive correlatioir \IXS formd to exist hctnwm the elevation of 5-HT content in tlic iiic~sotlienceplialoiiand the EEG changes c ~ u s e dby 5-HTP, and ;L continuous theta rhytliin ( a n d a dPs)lnclilonizatioii of tlie nwcortical activity ) occurred when the 5-1 IT content in t1w mid-brain slrowetl a threefold increase. 1 1 ~ - 5 ~ I ~ ~ t l i y l t r ~ p t o p which l i a i i is not a prcciii-sor of 5-HT neither caused EEG changes nor did it altcr tli(1 5-llT content of the brain. No plausible cxplanation can I)c oEercd for tlie fact that a5-I-ITP: lien injected intravenously, caused a disappcarancc of the theta rliythm and rlrinenceplialic spike discharges wliereas, wlicn injcctcd intracarotidly, it inducctl ;I latc. arousal reaction with a theta rhytlini in the liippocampus.

3. Tryptnniinc Tryptaniine is mentiontd lwre since. its action on the. KEG, and c~speciallyon the 1iippocatirp;il acti\ity, is very siinilar to that

128

CH. STUMI'F

of 5-HTP when both tlrugs are given in comparable intravenous doses to rabbits. Single doses of IS to 25 mg/kg tryptamine produce in the hippocampus a flattening associated with disappearance of the theta rhythm and occurrence of spiking but, in contrast to 5HTP, these changes last for about 5 minutes only (Domer and Longo. 1962; Longo, 1962). The tryptamine-indiiced depression of the liippocampd theta rhythm is asociated \L it11 a marked deciea\e of the spontaneou~ firing rate of pyramidal neurons. Often, at tlie peak of tryptamine action, these neurons do not discharge at ,111. Neurons in the subiculum behave as pyramidal neurons do. The spontaneous firing rate of granule cells of ihe dentate gyrus, on the other hand, shows frequently a tremcnclous increase under tryptamine. The firing rate of these neiiroiis may increaw to such a frequency that intermittent prolonged partial tlepolari7ation of tlic cell membrane occurs (de Harm et d.,1963). It will be recalled that, undcr LSD, granule cells also beliavc differently when conipared with p j ramidal neurons althougli no increase in the firing rate of granule cells w a s observed under LSD. Possildy, the tr) ptamine-indut ed discharge pattern of granule cells is in some way related to the hightrcquciicy spike clischct~ ges in the liippocainpiis EEG. It will be notcd th'it in n ~ a n yrespects tlre actions of ISD, 5HTP, and ti yptamine on the 1iiplx)cainpal activity and unit firing pattern have becn found to 1c, similar. In tliis connection it is of interest that according to Curtis and Da\is (1962) all three drugs depress ortlioclromic rwitation of ncurons in tlie lateral geniculate nucleus of tlie cat w1ic.n applicd elcctropliorctically close to the nciiron under observ at'1017.

IV. Conclusions

and Summary

The question may wc~llbe poscd whether any useful conclusions can be drawn from the consideration of the actions of various drugs on only one area of the brain. This may lie done, however, if certain limitations dre kept in mind. In any event, tlie consideration of the actions of drugs on the hippocampus has allowed tlie separation of tlrugs with probably different modes of actions where this has not been possible by the stndy of cortical or brain stem rhythms. The aim of neuropharmacological experimentation of any kind is primarily to clarify tlie mode and site of action of the drug under investigation. The hippocainpii\ is connected by afferent and effer-

ent pathways with many otlicr Ijraiii arcxs and, tl~crcfore,a drugintliiced change of hippocampal acti1.i ty docs not nec cate a drug action on thc IiiL)l)o(‘;~i”i~iis itself. For instance, the Iiippocampiis receives iii1pulsr.s fro111 tlie brain stem reticular forination, a s d o the ncocortex :ind otlicar I)rain arras. Conscquently, any drug which acts upon thc rcxticuIar forination, may modify the liipliocanilial activity, just a s it m a y inodify the electrical activity of the neocortex and other braiii areas. Problcms concerniiig drug action on the reticular formation have tloliberately been touched upon only rarely in this revicw sincc changcs of hippocampal activity due to the action of drugs on th(. rc,ticular formation would comprise only a small part of tlic Elhanismsof action, can provide clues to thc nk!ture of the basic ph>.siological mechanisms. Although thcre havc been niiincwus studies of drug effects on learning during the p":jt several decades, rescwch in this area has been particularly acti1.c during the past fvw years. This review summarizes representative studies of the effects of clrugs on learning and memory in infrahumans. It is not comprohensive, but instead emphasizes research concerned with the bases of drug effects on learning and nieinory and the relc\mcc of the findings to curront concepts of meinory storagc mcdianisins.

A.

PERI'OR1\IAKCE,

LEAI\SISG. hSU

R'II;.' V0Fi-l

Thc inost crucial problem in research conccrning drug effects on learning and mcmory is that of distinguishing tlriig effects on Zcarning from other ef€ects of drugs on performance. M7hat distinguishes learning from performance? It is clcar that \\.hen the word "learning" is used, it refers to a cliaiige in hehavior which is brought about through practice. It is also clcar that not all changes in behavior that appear to occur as a function of practice should b e included. Changes in performance as a result of physical growth, effects of fatigue, or changes in motivation are clearly not instances of learning. The distinction l)etu7ec~lcwniiig and performancc \\'as llrought into sharp relief by experiments oil latcnt learning. In an early latent

EFFECTS OF DRUGS O S 1.1; \ R V l S ( ; A S D ?rIE?rlORY

141

learning experiment, Rlodgett ( 19.79 ) gave. three groiips of rats o m trial each day in a simple mazc’. Onc gr(~iipwas rewarded in the goal box on all trials, a second group \zas not rewarded until the seventh day and then on each su1)scqucnt day, and a third group was only rewarded beginning 011 the third day and then daily. The animals in the first groiip showed a gradtial drop in errors at the outset, whereas the error scoros for the other two groups remained high until thc day after the first time they found food. At that point the error scores t l r o p p c ~ l\ w y suddenly and were almost immediately coinpara1)lc to thv scores of the first group. Thcwfore, it appears that thv aniiirals i n the second and third groiips had been learning much morc than their pcrforinancc~shad i n d i c a t d during the nonrewarrled trials. h i t that the leariiing hat1 remained “latent” (i.e., not indicated by performance) until thc. reward n7as introduced. Subsqiicwt cqeriments ( e.g., Tohnan and I-Ionzik, 1930) obtained esscmtially similar results. [ See Thistlcthwaite (1951) for a revirw of thc cL\;tensive latent learning literatiirc..] These findings indicate quitc, cl(.arlv that although learning must be inferred from performancc~,Ic~irningis not ahvays evident in performance records. Often, the problem of definiiig those changes in behavior which can be considered as evidenccxs of learning is solved by offcring an opcrational definition in \vhich thv tcvm learning is defined by a set of operations. These opcratioiis iisnally arc measiircments and proccdiiral descriptions which c~sta1)lisliconditions for IISC of the term. Strict operationism maintains that “. . . in general, we mean by any concept nothing more tlraii ii sclt of operations; the concept is synoii~mouswith a corresponding set of operations” ( Rridginan, 19%). Objections have hcen raised to the application of strict operationism hecause it is deciuctl fimdainentally circular ( Popper, 1959). Nevertheless, regardless of tlic position taken about strict operationism, it is inescapable that an!’ concept that is to bc studied empirically must, at the point of c’sl”rimentatioi~, have an operational translation. Usually, wlien operationally translating the coilcept “learning,” some arbitrary performance criterion must be chosen. It has been shown that tho nature of this criterion can affect greatly the results obtainctl. Tlie conclusions drawn from a study may be entirely specific to the critc,rion chosen. For example, H E ~ L( 1959) has sliown that anticholiti(’rRie drugs will abolish a

142

JAMES L. MCGAUGH AND LEWIS F. PETRINOVICH

conditioned avoidance response early in the acquisition process, but that they have no effect on a well-established response. Studies of learning typically emphasize improvement in performance with repeatcd trials, Thus learning is usually identified by responses which are repeated. As the findings of the latent learning studies indicate, however, learning can occur without the repetition of specific “correct” responses. Further, in many stndies evidence of learning is based on observations of variations in responding. In response alternation learning ( e.g., Petrinovich and Bolles, 1957) and one-trial avoidance learning (e.g., Essman and Jarvik, 1960), degree of “memory” is indicated by the tendency of the animals to avoid making a previous rvsponsc. ‘l’he nature of the memory trace or “engram” underlying the capacity of aniinals to either repeat or vary their responses a s a consequence of espcrience has been the focus of many recent ~~sy~liopharmacological studies. The main interest has centered 011 the nature of the processes involved in memory storage. This research has required the development of tcchniques for distinguishing those driig effects on learning that arc duc to effects on memory storage from other cffects due to attentional, percqtiial, and motor influences. Failure to provide for such distinctions can rcadily result in faulty inferences concerning the bases of clrug effects 011 performance.

InfEzrcnce of Research Focus Research concerning druz effects on behavior tends to be focused alternatively ‘on either pharmacological questions or on psychological questions. Most of the research employing operant conditioning teclniiqucs is done with a pl~arinacologicalfocus. The operant response is often chosen as an assay technique because it is very reliable and easily quantified. The (Beets of various drugs may be evaluated by a study of the changes in the rate and pattern of response in the light of variables in the reinforcemcnt schedule. This kind of research yields sets of perforniiince curves which can be coinpared to one another readily. These coniparisoiis make possible the classification of drugs in terms of behavioral effects. However, this approach often uses the rate of perforinnnce of a strongly established response as tlie depentlent variahle. The animals are usually pretirainccl on a simple reinforccine~~t schedule until very stable rates of respoii(1ing arc. ol>tainecl hefore the drug

conditions are introducrd. ~ : o i i s c , c l ~ i c . i i t l ~the . , results are not liery informative about tlic acquisitioii proce This is, or course, a result of the focus of tlie rcw~arcli.Tlicb (11i iasis in such work is on factors affecting tlie pc~rforiiiaiiccof IiiqIiIy Icarned responses, and risri:iIly i i o inference is drawii rc9gartIiiig the nature of any unclerl!.iiig ps~cliological or ~~s!~c.lro~~li~~sioIogic~al principlvs conc~crniiig ltxrning. :I rrrlrcli smallrl. a ~ n o u ~ iott I C . S C . ~ I . C ~lias I I)een d o n c l iisiiig a psychological focns. 1 icrc,, the so;rI is t o study psychological 01’ ps~~liol’l’ysiologie~~l processes, siic.11 215 tlic nccessary a n d sufficient coiiditions I’or thc storagc of incvnor!. t r a c u and for their retrieval. \\.it11 tliis focus, the drug 1)tcoinc~sInit oiie of many tools. Research \\.it11 a ps!-cliological focus tends t o cliaracterized hy closer atteiitioti to tlic pol)lenis of opci.;rtiotiiil translation ( see : i b o \ ~ )This . permits systcinatic stud!, of tlrc, lxisic. Ixiranieters iiivo1vc.d in leariiing, sucli ;IS the effect ot 1 I i c 1 r.r~lati\-c~ inassing o r distri1)ution of pr;icticv. \I’itli tlie al>ovc priiicipl(5s i i i niirrcl. let u s re\ie\v some early esainplcs o f drug rc-searcli oii I(wiiiiig. Tlie merits, a s well as the sliortcoinings, of tliis \wrli \T,ill s c ~ \ ~; I(S ~ mi introdnction to the currciit sirrvc’y \vliich follo\\-s. 1

H.

x

1taincd additional cvidcncc, t h a t t i x i / ( > ant1 discrimination Icarning can I)c facilitatctl with 1imttri;il iiiicx,tions ol' 1mit),l(.iictc.trazolc

( hlcGaiigh, 19651)) , Iicc.cmtl!~ 1~alim:inn( 1963) stridicd t l i v effects of caffeine oii tliscriniinatioir lcariiing and transposition l y liamsters. Learning ant1 rctcwtion \\'ere facilitated by lm'trial iiriwtions of 0.5 mg/kg ( sc) a i i t l iinpaircd ivitlr larger c1osc.s ( 1 .O-10.0 nig/leen cstal)lislitd ( 13orek c,t al., 1950; Jcrvis: 195O), \xioils iiivestigators I i a \ . c l trtxttd plienylpyruvic chilclren with a pht~nylalaninr OW diet m i d s o i i i c ~i i i ~ ~ ~ r o v e m of c n tboth inental as \re11 as physical conditions Ii;t\.c> Iwtm rcported ( Hickel ct a!., 2933; :4rmstrong and Tyler, 1955; \\'oolt ('f ul., 1955). I n 1954, Armstrong autl 1iol)insoii otfered e\klence of ail abriorinal intlole inetal~olisniin pliviiylpytrivic oligophrcnia including inc.reasc,cl urinary escrction of iiitlole,-:3-ncctic acid and decrcased urinar!, lcvc~lsof 5-liydrosyiiitlolc.ac.c.tic acid. Rrune and l-Iim\vich ( 1960 iisiiig quantitati\,e inctliotls cl~tc~i-~nincd total indole-3-acetic acid a i i d tryptamiiie i i i two 1)11(%1 i!.ll-3

X

2 4

~_________

0

0

0 3 4 2 3 6 6 6 6 6

0 0 2 1 2 4 5 5 6 5

M

2 0 2-3

1-2 1 3

4 3

2 1-2 2

2 6 6 6 6

6

4

5-6 5-6 5-6 6

0 0 2 r r ) .?-9

0

1

0

2-3 1

W

W

W

1 2

5

4-5 5

4 0 0 2 2

5

0-1

0

1

1

1

1-2

2 0 0

4 6 2 5 4

0 3-4 0

4 X XI

X

3 0 0 3 -4 1-2 0

A neurolcptic drug is said t o be “specifically active” in a given screening test when the intensity of catalepsy observed at the ED5”level is low, i.e., mean catalepsy score 0 to 1. Its action is said to be “aspecific” when the mean score for catalepsy is high, i.e., 5 or 6. The symbol m indicatw lack of activity at the highest (siibtouic) dose level tested.

s:

1 r

? 7

+

L(

5

v)

2!

cataleptic immobility in mice, rats, dogs as well as in other laboratory animals. Table V gives the ranking order for cataleptigenic potency (chlorpromazine = 1) in rats. 2. A t low dose levels, not significantly affecting gross behavior, a typical neuroleptic drug is a “specific” blocker of learned conditioned avoidance responses, e.g., in the jumping box test (Table V I ) . In Table VII the potency ratios (chlorpromazine = 1) are given. 3. At dose levels producing a moderate degree of catalepsy, a typical neuroleptic drug inhibits food consumption in the AWtest and decreases rearing and ambulation activity in the open

Trifluperidol Haloperidol Flriphcnazinr I’erphenazine Reserpine Prochlorperazine Chlorpromazinc l‘hioridazinr Promazinc

;:5 15 35 0.5 4.5 I

0 ~

1~.

20 1

i 11

Open field test

Drug Triflriperidol Haloperidol Fluphenazine Perphenazine Reserpine Prochlorperazine Chlorpromazine Thioridazine Promazinr

Al.l:-Tr(.i701 Mufioz and C;oltlstcin (1961b) and Goldstein and M u l i o z (1960, 196lb) fonnd that this. compomd, at dosc~s of 1 to 5 pg/kg, iv, produced short-lasting stimulant c>ffccts in most of the animals tested (rabbits, cats, clogs). The cffcct coincided with the inasimal hypotension and tachycardia iiidiiced by isoprotcrmol, but disappeared before return to norniotensioii. L)encwation of thc carotid sinuses ( i n rabbits) shiftcd the effect from that of stimulation to one of sedation.

2 . nicliloloisopr.oteicnol ( DCI ) The same authors found in rabbits that 4 ing/kg ot this structural analog of isoproterenol (which characteristically effects betaadrenergic blockade) produced rnarkcd and long-lasting arousal effects, as nwasured b y reversal of pentobar1)ital-induced sedation. Sniallc~d o s c ~had only a partial reversing eff cct. 3. Amplietaniiric Mufioz and Goldstein (1960, 1961a) a i d Beck ct 01. (1963) performed extensive experiinrAnts with amphctaniine administercd to rabbits equipped with chronically implanted electrodes and methodically trained to withstand intravenous injections under minimal stress and unr'estrained conditions. To ensure the delineation arid precise 111ea!iure11ie1it of drug eff cct, the rabbits ~ ' e r c initially lightly sedated with 3 nig/kg, iv, of sodium peiitobarbital, thus inducing an acceptably constant lcvc~lof hypersynchroiiization. Varied doses of amphetamine were given intravenously immediately thc~eaftcr-one dose level per group of 5 to 10 animals. The degree of stimulation was determined by the rewrsal of tlie lcvc~lof the hlEC of tlie 1,arbitiirate-induced sedation toward the RlEC Icvel existing during tlic control period prior to sedation. Applying siich an experiinental proccdnrc, linear log-close-effect relationships could be demonstrated on appropriately plotted curves; from tlic latter, in turn, 50% reversal doses (of pentobarbital sedation ) could be determined to serve as relative indications of testdrug activity. This, tlic average dose of d-amphetamine required to produce a 50%revcrsal w a s foiuitl to be 0.01 i0.005 mg/kg.

The aforementioned relationships enable the evaluation of the stimiilant effect to a more prccise dr.gpe than possible with qualitative observation alone in \vhicll oiily cxtensive change can convincingly carry significance. The rff ects of n-amphetatiiiiic: i n iiormal human subjects were stiidicd b y Pfeiffer ct 01. (1960) ant1 XIiirphree et al. (196211). The EEG \\.as rocordccl from the pariytal x v a ; ineasureinents for analysis wcrc obtained by “sampling” tlw record for 5 minutes at 30minnte intervals for a period o f 3 liorirs. In 7 subjects, 0.1 nig/kg, iv. prodiiccd a significaiit dccrcmc~in the parietal EEG after a short latent period. u7itl1 15 mg per os ( 8 siilIjccts) a significant change was also d(~tc~ctcd, this time in the ocripital area; the stimulant effect was not, ho\vever, consistcntly prvsc-iit aiid acquired significance only \vlien the total data obtaincd from all 8 sulljects were averaged. The measured EEG changes anioiintcd to a 20% decrease in the hlEC and a 20% decrease in tlic CV. This effect first appeared in the recorded electrical activity i i i a IO-minute “sample” obtained 30 minutes after drug administration, attained a peak at 60 minutes, and returned to the control lc~vclaftor 2 hours. 4. Deci nol ( 2-nimctl~!/Zaminoct7f(iriol) Primarily, dcanol is a precursor of choline ( trimethylaminoethanol) which has I~ecns h o \ v ~ I)y i Croth ct al. ( 1958) to pmetrate the Mood-brain liarrier freely. Cliolinc~,in tiirn, is known to be a prcuirsor of aectylcholinr~, a iit,iiroch(,inical inediator important for maintcwxncr: of the vigilant statt. o f the organism. Chldstc~in( 1960b), Pfciffcr rt ti!. ( 1.963),and Beck ct al. (1964) stiidicd the effects of this c o i n ~ ~ ~ i ~oni rthe ~ c lrabbit EEG. The action of d c w i o l appears to depend on the Iwhavioral state of thc animal at the timc of driig adininistration. A tlosc of 5 mg/kg, injected intravenously, into awake, spontanc.orisly alert rabbits, produces within 20 to 30 minutes, an E I X consisting of sporadic “hypersynchronus” patterns corrcqIondiiig to incrcwcs in both MEC and CV. Administered to animals, tithcr s~~ontaneoiislysedated or pretreated \vith minimal dosc~ of I”.iitol,arbital, the same intravenous close of deanol produccd, aftcsr ;I 15 to 20 minutes latent period, a distinct and suddcm shift in the EEG pattern toward stimulation. Dose-tdFect ciirvc’s, t~stablislicd by the expcrirnental tlcsign drscribcd previorisly for amplic.tarnine, revealed that the tlosc~ of cleanol exerting a 50Y r c ~ v c ~ s aofl scdation \\,as 1.8 s 0.5

286

LEONIDE GOLDSTEIN AND RAYMOKD .4. BECK

mg/kg. Of interest is the fact that monomc.thylaminoethano1 produced the identical reversal at the much higher dose level of 13.2 mg/kg. This tends to indicate, for certain compounds, a relationship between the degree of methylation and their stimulant potency. Other examples of this type of structure-activity relationships are to be mentioned later. In man, the effects of single-dose administration of deanol were studied by Pfeiffcr ct al. (1960, 19G4b) and by Goldstein et al. (1963b). The dose most frequently employed orally was 200 mg, although in several cases the effects of 1-gin doses were studied; also, on a group of 7 subjects, an intravenous dose of 1 mg/kg was administered. In regards to the MEC, the EEG changes observed were very similar to .those produced by d-amphetamine, i.e., a decrease attaining its peak (20%) 1 hour after drug treatment. However, exactly con{-rary to the pronounced decrease in CV occurring with amphetamine, deanol increased the variability of the EEG energy levels to 120%;this altered variability still cxisted 2 hours after drug administration, although the MEC had since retiirncd to the control lcvel. Chronic administration of deanol n7as effected only in male chronic schizophrenic patients, as part of a year-long study involving cliffercnt drug treatments, to be described in detail later. Sixtcen patients, not cxposed to any aciitc or chronic driig treatment for at lcast 3 months were involved in that stiidy. Their h e - l i n e recordings had the typical characteristics of a very small CV, of the order of 7%.Deanol ~ 7 a sadministered daily at the oral dose of 1 gni. Recordings, performed at the end of 1 nionth of such treatment, revealed a 30% increase in the CV of the group. There was, however, no significant change in the over-all MEC and no changes in behavioral ratings (Sugerman et al., 1964). C. OTHER TYPES OF CNS STIMULANT DRUGS

.4 number of compounds were stucliecl i n rabbits for possible stimulant properties by Goldstein (196013) and Beck et al. (1964; Beck and Goldstein, 1964). In most cases, dose-effect curves were established by the procedure applicd to the study of amphetamine. 1. Tropines Of this group of compounds, atropine arid scopolamine are of special interest in that they are known to produce behavioral stimulant effects (in many species) along with a seemingly contra-

dictory hypersynchronized pattern in tlhe EEG. As a matter of fact, it is in reference to these sliwific compounds that the exprcssion “dissociation between EEG and 1)cJliavior” was originally used ( \Vikler, 1952). Atropine, 1 nig/kg, iv, did indeed shift the normal pattern of the EEG to\vard a typr rescmibling cither sedation or light sleep, Howevcr, statistical analysis of tlie qtlcltztitatetl EEG revcded an important diff ercmcts lwtn 11 thc two types of hypersynchronization, inapparent to obsrnxtion with thc naked eye. CJndcr true sedation, the distril~ntion of successively measured pc’riods of electrical energy ( pcbriotls of 1-second duration ) was tnarkcdly widened in comparison to its spread during normal wakefulness. Under atropine, ho\vevclr, thc limits of the distribution rcniained unchanged from that 1id‘oIc. drug administration; rather, thia “sedation” effect consisted in a shift of tlie entire system toward highclr values of electrical energy. Furthermore, if the dose of atrol’iiit, adtninistvred is dccrcascd to 5-10 pg/kg, the lichavioral stimulant effect of higher doses again appears; but now, in eontradistirictioii to high-dose effect, the EEG pattern is that of a loiig-lasting d(,synchrotiization. Thus it was established that in the parainc3tt.r of thc EEG, atropine liroc1iict.d two opposite effects dependrnt on dosc: level: at 1 to 50 pg/kg, a progressively increasing stimulant e1foc.t prevailed ( a s eviclenccd by thc: per cent reversal of peiitol~arl~it-al-ii~d~i~ecl scdation ) ; whereas, doses above 50 ,~g/lig~iroduer~tl, i i i place of the low-dose arousal, a deepening of the scdatetl state. ‘I‘ltc same relatioiisliips werc found to occur with scopolaiiiine esccyt that the dose level thresholds for arousal and setlation \\’ere one-twelfth-to one-twenticth that defincd for atropine.

2. Plzysostigmine This cliolinesterase inhibitor cxcrted a distinct stimulant effect at a threshold dose level of 20 ,Ig/kg, iv; the effect lasted 30 niinutes. From preliminary unpuhlis1ic.d ohscrvations, it appears that unlike all the chemical compoimds discussed in this review, physostiginine studies do not yic3ld dosc-cBc>ct curves, thus implying the existence of an “all-or-none” plienomenoii. 3. Nicotine The dose of nicotine produciirg ;I 3)X reversal of sedatioii \VRS found to be 19 pg/kg. It is t o Iw c~i~iphasizecl that contrary to the action of most stimulants, t l ~ offects , of this alkaloid were found

288

LEONIDE GiDLDSTEIN A N D RAYhfOND A. BECK

to be extrenicly short-lasting, appearing 2 minutes after intravenous administration, and disappearing completely within 6 to 8 minutes (Beck, 1965).

4. Caffeine Only preliminary data are at present available concerning the effects of caffcine on animals. It appears that tlic 50%reversal dose is apl~rosimately1 mg/kg, administered intravenously. ,4 significant effect liccomes evident after a latent period of 3 to 5 minutes and persists for a relatively long period of time (30 minutes or more). In normal human subjects, the effects of a single oral dose of 250 mg of caffeine wcIe studied b y Goldstein et d.(1963b). The EEG stimulant chffcct appeared vcry rapidly, attained an approximate maxirnal point :30 minutes after clrng administration, and persisted for at least 3 hours. The obscwctd changes resembled those produced by aniplietamine except that thcy were comparatively inore acccwtuated; that is, caffeine induced a 30% decrease in thc MEC, and a 35%decrease in the (3'.Unlike their response to all subjects reacted to caffeine essciitially in the amphc~taiiiinr~, same fashion and with little variation.

5. I 3 11 le ti ctlio tti ii I CJ Coinpo 1 I ti rl.s Bcck ct nl. (1964) :;tidied a series of iiiethylatcd derivatives of ctliylciicdiarninc to ascertain the degree to which progressive methylation may promote siniulant properties of the cthylenediamine moiety. As in the investigations of drugs already described, the cff ective potency of each siibstitutcd coinponnd \vas cwluated in t e r m of the dose level producing a 50%reversal of pentoliarbitalinduced sedation. The results deinonstrated a direct relationship betwwn the dcgrec of methylation of tlie amino groups and the stimulant effect evoked. For cxample, the 50%reversal dosc of the N-monomethyl derivative was 36.0 iiig/kg, iv, as cornpard to 5.7 nig/kg for the trimethyl compound, implying increasing stiinulant potency with progressive methylation. 6. Iboguinc This alkaloid extracted from the shrub Tabernurrthe i h g c i \\'as tested by Droliocki ( 1954d) in inan. Monopolar EEG recordings tverc obtained from the vertex; the integrator pulses \\jere mcasured

in units of 1-sccond timc. iirtcmds. Sigiiificant changes \\WC Wflected in the spread of the distril)ritions, in the position of the mean, or in both parameters, and occ.iirr(d chicxfly at tlie time the subjects r t y o r t ed “11sy diic ciscit a t ion .‘’

D.

. - \ S . I , ~ D I ~ I ’ H I ~ S S A SA T Acxsrs

At the prescwt tiinc, aiitit1cpi.c tiit drugs investigated in nian include only the monoaininc, oai s(: inhibitors, tranylcypramine ( 20 nig total dosc, orally), and the experiinental coinpulid, 2inetliyl-3-~~iperidinopyrazineor \!WO7 U ( 50 and 1% 111g total doses. orally). The results of tliese stutlics were essentially negative (Chldsteiii et al., 1963b), as slio\nrn b y no significant change in hlEC or CV over a 6-hour pcbriod, o t l w than a transient increase iii the h\IEC 2 hours after th(2 larger 130-ing dose of \V3307 13. 1 I O \ W ~ C T ,clinically, these anti ssant drugs are \veil kno\vn to bc slo\v ill onset of action, I ‘tating rclatively prolonged administration to evoke the desire iavioral efftxts. Hence, it is not surprising that, in thc abovc~stiidy, quantitated EEG cl~anges wc.rv undrtc~ctahle following a singlcJ-dose administration and a relatively short period of EE(: rccortling. IX. Analysis of Changes Produced b y Hallucinogenic Drugs

EIW since the discovery of tlrc rvinarkable capacity of lysergic acid dietliylainide ( LSD) to iii(1iicc Iiallncinatory statrs in inan, there has 1,een coiisiclcm1,le intcrcst i n this spwific coiiipoiind, and others v.ith similar activity. Altlioiigli l~roiniiient chaiigi~s \$ deinonstrated in the EEC’s of aiiiinals under tlic influence of LSII, mcscalinrl, aiid psilocybin, distiiicti\~cfcatures in tlie clectrical activity of the hninan brain could not l x t dctc~ctedhy visual inspection of records alone even dining thv o c ~ ~ i r r c n cof e drug-induced lialhicinations. Hence, the qnaiititative nivtliod of EEG analysis was applied in an attempt to i n i v o v ( ~tlicx ;ipparently sn1)tle cffects of halhiciiiogenic drug action. ‘4. ESPERI;\IENTATION I N MAN Goldstein et al. ( 1963a,b) ntlrniiiistcwd LSD orally to norinal volunteers at the two dose Icvols of 0 . 3 and 1.0 ,.~g/kg.Ten-minute recordings were obtaiiicd from tlic left occipital area every 30 minutes for a period of 3 hours. As in all quantitative EEG studies, electrical energy levels and tlic varia1)ilitics therein were expressed

290

LEONIDE GOLDSTEIN AND RAYLfOpLD A. BECK

in relation to their conirol levels in a fixed period to drug administration. After the 1owc.r dose of 0.3 pg/kg, the 6 subjects tested reported no behavioral eff ccts other than a slight restlessness. Further, no significant change in the MEC of the quantitated EEG was detected during :any of the sampling periods. However, a significant decrease in the CV (from the control value of 17.6 to 11.7%) occurred 90 minutes after drug ingestion. This lowered variability was still detectible after 2 hours. At the higher dose of 1 &kg, producing visual hallucinations and other LSI) effects in most of the 13 subjects studied, thc decrease in EEG variability was w e n more pronoiiincrd (from the control value of 14.7 to 7.9%). Moreover, along with this change, the level of the MEC decreased liy 93%. hlaxinial decrease in electrical activity occurred in 90 minutes; that of the CV, in 150 minutes. Thus, in the quantitated E E G s of nornial volunteer subjects, LSD does, indeed, induce prominent changes. The latter are similar to those observed with amphetamine and caffeine: a decrease in MEC and variability; the decreases, however, were relatively pronounced and longer lasting with LSD. Of interest at this point are the experimental reports that overdosage with amphetamine may produce visual hallucinations. Also to be considered is the fact that the decrcasrct EEG variability typical of drug-induced hallucinations is very similar to that found in the resting EEG of the chronic schizophrenic. In both cases, the variability is approximately one-half that found in normal, untreated subjects. Goldstein e t ul. (1963a) administered LSD (1 pg/kg orally) to each of 10 malc chronic schizophrenics. There was no change in the MEC during 2 hours following drug administration. On the other hand, the CV increased rather than decrcased, as occurred in the nonpsychotic subject. This could be interpreted as a “rebound” phenomenon, although no striking behavioral changes were observed in the paticmts tliroughout t h t period of action of LSD.

R.

EXPERIMEXTATION IN

ANIMALS

The effect of hallucinogenic drugs on rabbits was studied by Picrre (1957), Goldstrin et 01. (1962), and Heck et al. (1963). As anticipated from thc findings in normal human volunteers, these drugs proved to be cqiially powerful CNS stimulants in rabbits. Using the previonsly described technique, and determining the

AMPLITUDE ANALYSIS OF THE EEG

291

dose necessary to reduce thr energy levels attained during pentobarbital-induced sedation by SO%, the following values w cw obtained: LSD-0.23 pg/kg; hifotenii ic--0.08 mg/kg; psilocybin0.27 mg/kg; mescaline-1.7 nig/kg. 111 all cases, the stimulant effect w a s long-lasting. Goldstein ct al. (196s) and P f t d h ct (11. (1965) compared in rabbits thc changes induced b y LSD at cortical and rhombencephalic levels to c1iaiigc.s occurring during “paradoxical” or “fast” sleep. This study \vas prompted by the observation that in both cases thc cortcs cxhiI)itcd a i l identical 1JLltterll of “liyperaroiis~ill” and that an uncl~iestionable rescinblance existed between dreaming a i d hallricinations. As shown by the work of Dement a nd Kleitman ( 1957) there are numerous indications that dreaming takes placca duriiig the stages of paradoxical slwp. Quantitative integration of thc EEG recorded during paradosical slc,ep rcvealed that thy cwc~gycontent and variability arc quite low at cortical levels and very Ir igli in the subcortical, caudal, pontine niicleus. Following ( 5 ,Lg/kg, iv), similar effects were seen at cortical levels, but in the rliombencephalic area, no significant difference from wakcfulncss was found in either energy content or CV. This could mean that different mechanisms (or perhaps cliff erent neuronal pathways ) arc. involved in dreaming and drug-induced hallucinogcnesis. X. Analysis of Changes Produced by Antianxiety Drugs

A. A N I m a STUDIES

Drohocki and Goldstein (1957) stiidied the effects of benactyzine, meprobamate, and the expwiniental compound, phenylparachlorophenyl morpholinoetho?ryiiictlie ( LD 2630 ) on the cortical EEG of rabbits. All three driigs prodiicml a shift of the I X G toward sedation, corresponding to increases in the IvlEC and (21’. The doscxs doiibling the control cnergy Irvt.1 (within a pcriod of 20 minutes) were: benactyzine--0.8 mg/kg; LD 2630-3.0 mg/kg; and iiic.l~r”bnmatc-1.0 mg/kg. Tlie drirntion of effect was longest with LD 2630 aird shortest with I)cwwtyzinr. The data in tliese studies \vcrc aiicilycd in a somewhat different inaiiiier. yieldiiig, as a rcwilt, ddi ti ot ial and unanticipated information; that is, successivc lO-scc,ond intervals of the EEG were measured, the time-unit w l i i ( ~ sciimiilatecl, and then plotted to

292

LEOSIDE COLDS1I:IPI

LUD RLYSIONI) 4. BECK

o1)tain linear regression lines, for the period of drug action (the first 20 minutes following drug administration). The slopc,s of the regression lines were found to be directly dose-related, suggesting a one-step relationship lxtwcen the close of the drug and thtb number of time units involved.

R . STLJDIESON NOHSIAI, \

i

~

)

~

~

~

~

~

~

:

A number of antianxicty agents were studied b y (.:oldstein (1963d), Pfeiffer a i d Schultz (1964), Pfeiffer and Goldstein (1964), and Pfeiffer ct al. (1964a). The EEC WRS csvaliiatcd from successive 10-minute units, sampled from the recording c\ for a period of 6 hours. As with most of the previous studies, incasureinents were esprcssed in relation to a 10-minute, p r ( ~ l ' u g , control recording.

ct

(11.

1. Alepsobanicite A total oral dose of 800 ing Lvas administcred to 10 normal volunteers. Two hours after drug administration, the h#lEC was decreased by :30Y; after 6 hours, it had returned to tliv control level. The CV, on the other hand, increased progressively and markedly, attaiiiing a peak in the fifth horir postdrug sampling. and still 25% above normal at the conclusion of the experiment.

2 . Chlordiazcpoxide Similar changes, i t . , decrease in MEC and increase in CV, were observed in the 9 subjects studied (20 mg total oral dose). However, the appearance of effects in relation to time differed from that of meprobamate. \Vith chlordiazcpoxide, the MEC was not significantly deercased until 4 hours after drug administration, nor did it return to control level at the conclusion of the 6-hour duration of the experiment. Further, the CV did, indeed, tend to increase, but significantly so only in tlrc second and sixth hour samples of the EEC rccord. 3. Di~~hciiliycl~aminc This antihistaminic agent was tested at two dose-levels, 20 and mg (total oral dose), on 10 and 13 subjccts, respectivcly. Sirnilar, though more pronounced, inverse relationships hetw,een the MEC and CV were olmrvecl as with meprobamate and chlordiazepoxide. For examplc., with SO m g , the M I X decreased. 6 hoiirs

~

~

~

after driig adininistration, to 284 ol its control valuc; at the same time, the C\.' almost doubled in valuc. In I d 1 EEG parameters, the degree of change was shown to I)c dosc~-rclated.

1. Orphenntlrine 'I'hc EEC: changes prodiicxd l)y tliis tlriig rescml)lcd those dcscribed for diphcnliydrainiiic.. Total t1osc.s of 20 aiid 50 m g , admiiiistercd to each of 10 and 1:3 sril)jvcts, rc~spctively,produced a similar tlecrease in the ME(: ant1 iiicwase in the C\'. Ho\vvrver, compared to aforemcntionc~cltlrrigs, orphcwidrinc effects \ w r v both tiiore acccmtiiated in natiirct m t l tliffc iitly spaec~lin time,.

3. Atropiiic OIICmilligram total oral tlosc, ( t l i c s sole dose levcl studied), aiigc in tlic h113C i ~ r ~ w i i r v cthroughout l a 6-lioiii. er, a signific:urt trcvrtl t o u m d iiicrcwc, iii the C\' \vas observrd.

6. f.:tl1anol Each of 10 subjects received ;in oral close of ctlianol amomtin:: to 0.25 ml/kg (95% soliitioir ) . \\'ithiti 60 minutw, the RIEC 0 1 the quantitatcd EEG dcerc!ascd by 17%';at thc: same time, a slight, nonsigiiificant, increase. in thv CV occwrcd. The maximal tlrop in hIEC appc~ircd90 ininiites aftrr driig athninistratioii.

7.

1'/1Pll

0l)crrhital

Total oral doses of 20 a i i t l 40 riig \VLW givcxii to each of 2 groups of 10 subjccts, respctivcly. l ' l r c ~ il+:C chaiiges again included a decreased IIE C and increased CI', 1)iit iinlikc tlic compoiiiicls discussed above, these trends \vcrc not iiiiiforin but prwwit(d, instrad, a varia1)le course of cvciits: 1 hour after driig administration, the hlEC dccrciased; in the secontl- ant1 tliird-hour E E G samples, the e i i r ~ g ycontent rcturncd to normal lcvcls; in tlic fourth hour, a scwond more pronounced decrcxse iii hIEC occiirrcd ( as coinpared to the first sampling), aiid persistctl t o the conclusion of the 6-hour experimental period. Since sampling errors are always possible despite the averaging of data on as inany as 10 siibjccts, I'fciffer (1965) repeated the same study on a n cwtirely new groiip of 10 siihjects. The rrsults o1)taiiird \ v c w strikinglv similar to thaw obtainecl for the first

294

LEOh'IDE G,DLDSTElh A N D RAYMOKD A. BECK

groups. i t would appear, therefore, that the biphasic drop in MEC under phenobarbital rrflects a characteristic fcature of the action of this drug. It is tentatively suggested that the second (fourthhour) dccreasc in RIEC may be due to the effect of a metabolite of phcmobarbital, cxerting stronger effects than the barbiturate itself. 8. Pciitobarbitul

T\\&y and 40 rng total oral dose produced no significant change in eithcr ME(; or CV throughout cxperimental sessions lasting 6 hours. As will lie discussed, higher doses did cxert significant effects, but of a nature morc characteristic of hypnotic rather than antianxiety activity. The decreased MEC induced by antianxiety agents iiiight, indeed, seem puzzling ( i f not paradoxical) when considered in relation to the CNS stimulant drugs which similarly effect a diminution in electrical activity. However, in contrast to the decreased CV observed with stimulant clrugs ( aniphetaminv, caff cine, LSD ) , variability in thc EEG :is increased with the antianxiety agents. Following admiiiistraticin of the latter, EEG recording examined by visual inspection alone, rcveal a pattern resembling that of drowsiness, namely, juxtaposi tcd intervals of alpha rhythm, nonrhythmic beta activity, and even sporadic slow waves of sleep. i n comparison, the state of arousal or stirnulation is characterized by a fairl!. constant reduction in lmin-wave amplitude persisting for a rclatively long period of time. It is precisely this differencr, in the variability of the quantitated EEG which distinguishes the action of antianxiety agents ( increasc~lC\' ) from that of stimulaiit agents (decreased C V ) . XI. Analysis of Changes Produced by Hypnotic and Anesthetic Agents

4. PENTOBARBITAL This familiar compound is of special importance in animal brain investigations in that it provides an effective base liiw of mild sedation to which stimiilant activity of varied agents can be more precisely referred. i n unrestrained rabhits cxpipped with chronically implanted intracranial electrodes ( parivtal cortcx ) and carcfiilly traincd to e y perimental proccdmcs, Muiioz and Goldstein ( 1961b). Pfeiffer et

~ 2 (. 1963), Beck et (11. ( 1963, IHfi-l), aiicl Beck and Goldstein ( 1964) foiind that pentobarliital in t1osc.s of 3 to Ci mg/kg, iv, increased the XlEC of the EEG to 200k or m o r c ~al)ovc~control levels. This effect rcquircd approximately 5 iniiiiitcss to r c ~ i c ha fairly constant level wliich theit persisted for 20 to :30 iiiinittcbs or more. The C\' was most often tlonbled. At higher doscy siicli ;IS 30 ing/kg, iv ( administered over a period of 1 minute), 1)rohocki t'/ (11. ( 195613) distinguished threc phascs in the evolution of tho h l I < C : an initial phase (lasting approximately 200 seconds aftcr injc~tioii) showing a decrcxase in hIEC; a swotid phase of rapid incrcwc. of hlEC (lasting from 300 to 300 seconds) ; and finally, thc alqi(waiice of a plateau of more or less constant activity. Plotting of the logarithmic: values of siiccessive l-second inter\xls of tllc second phase of rapid increase in MEC yiclclcd a l i n c m re-grcssion, which, in turn, indicated a geometric progression of tlic: nieasured vahics per time unit in the development of tlic hypnotic c>ffcct. In man, pentolmbital effects wcre stiidied b y Droliocki ( 1957a), Jenney et al. ( 1962), h l i i r p h r c ~c>t ~ (11. (1962a), and Pfeiffer ct d. ( 1965 ) ,

1. h'ormal Szrbjcc.t.y (A'

13) =\ total oral dose of 200 1ng protlticcd a phase division of the MEC levels as obscmwd in ral)l,its, iraincly, an initial decrcasc. ( dnration-12 minutcs ), ;I gcwiiivtric.-type increase ( duration-19 ininutc>s), and a slow arithnic+c iiic.rc:isc. requiring 6 minutes to reach the maximal l e w l of a platc.aii. :21r additional, primary stage ( duration--7 minutc,s), not sc.cm i i i rzhbits, corresponded to a latency period lx>twecn adnrinistratioil of drug and beginniiig of effect; this diffcrcncc> is, ho\wv(,r, most likely due to the difference in routes of adiiiiiristlatioii, naint~ly.iiitra~~enous in the rabbit, oral in man. The maxiinal Icvel of c,lcx.trical energy at plateau level averaged SOT, above that of the, c ~ ~ i t r oIwriod. l The CV increased both during the pcriod of 1ntc~irc.y ant1 during the first phase, of -

the rise in RIEC; it was furtlwr arifiinentcd during thc phase of arithmetical growth, remainiirg consit1cnl)ly elevated thereafter.

2. Male Chronic Schizophrenics

In this group, rcspoiise to l)('i~toliarl)italwas characterized by ), and absc.iice of initial c l ~ ~ e a of s r tlic hlEC. Thc gc~onictric-type increasc was re-

a relatively prolongrd latent period ( 22 minutes

296

LEONIDE GiDLDSTEIN A N D HAYhlOND A. BECK

placed b17 an aritliinetic progression of 17 minutes duration, leading up to a platean of iconstant activity, but only 25% above control level. Variability was unchanged during the latent period and only slightly higher during the two last phases.

R. THIOPEZITAL This drug was stuclied only in human subjects.

1. Nornial Subjects (A7

10)

A dose of 1.5 mg/’kg, iv, rapidly administered, produced an immediate, short-lastinq but very marked increase in energy content. Attcr 2 minutes, the hlEC temporarily returned to the control level atter which it decreased over the next 10 minutes by as much as 90%of its control value; the behavioral correlate of the t referred to as “activation.” recluccd energy period w‘is t h ~ usually As expected, it corrcspondcd to a rcduction in EEG variability. 2,.

Mnle Chrotiic Sch iz ophrc 11 ics

Somewhat similar changes were found in the averaged EEG data obtained from 10 patients. Howevcw, rccordings of the latter d in electrical displaycd a greater and more ~ ~ r o l o n g ereduction energy and variability than did no1 ma1 ( 1937) reported potentiation of the analgesic effects 0 1 inorpliiiw b y conipoi~iidssiicli a s cholinc and ncostigminc. It sccwied ol intcrcst to cxainiiie tliv statistical significance of this ~ ~ l i ~ ~ ~ i o ~and t ~ ~flirther, ~ t t o ~ to i , esplorc othcr coinpoiinds for possibly siinilar action. Thus, C:oldstrin (1960a) designed appropriate cxpcriiwtits on rabbits e q i i i p p d with clironically iinplanted c1cctrotlc.s a i i t l carefully traiiicd for their consistently steady rcspoiisc’s to srdatiw and stitnnlant qcvits. Thv first stcp in this work \\’as to tlvtcrminc- ii dose level of riiorphiire which odd h a w al)soliitc,ly no effect on hie ICE(:

300

LEOSIDE COLDSTEIN AND RAYMOND A. BECK

whetlicr administercd ~ n c eor two or three times tlirougllout a 12hour period, thus preduding cumulative action. Such a level, which provided a “base line” for measurement of morphine potentiation, appeared to he 0.05 mg/kg, iv. Similarly, potential potentiating agents were necessarily screened to establish threshold doses which of themselves also had no effect on the cortical electrical activity. Finally, interaction studies were performed to determine the most effective time spacing of tcst drug and morphine injections, this interval being obviously dependent upon tlic mechanism of action of the chemical compoimds involved. By such mcthods, ;I large series of quatcmary ammoniiim compounds of widely differing pharmacological properties, wtsre shown to potentiate or enhance the central action of morphine. These include: atropine methyl bromide, scopolamine methyl bromide, homatropine methyl bromide, methantheline, cl-tubocurarine, decamethonium, succinylcholine, neostigmine, choline, and methacholine. On the other hand, tertiary ammonium analogs of some of these drugs ( atropine, scopolaminc, homatropine, pliysostigmine) and other unrelated tertiary compounds (hexamethonium, mecamylamine, p-erythroidine, phentolamine, ergotamine, and dibenzyline ) were entirely devoid of potentiating properties. This study offers an unbiased confirmation of the Knoll and Komlos hypothesis which views such potentiation as an occupation of morphine receptors by nonspecific, quaternary ammonium compounds in addition to morphine itself, resulting in an additive analgesic effect.

c. ADRENERCICBLOCK1ERS-CATECHOL.4hlISES

AND

RELATEDCOMPOUNDS As previously mentioned, Goldstein and p\/luiioz ( 1961b) and Mufioz and Goldstein ( 1961b) performed numerous electroencephalographic experinicnt:; on rabbits to determine effects of adrenergic antagonist agents in relation to the reactivity of the adrcnergic system of the brain. (Eithcr curarized rabbits or waking, unrestrained aninials with ‘chronically implanted electrodes were used.) These studies were extended to iiiclude an investigation of adrenergic antagonists and are summarized as follows: 1. Epinephrine and norepinephrine produced significant arousal reactions in only 2OA of the animals. 2. Following prctrcatmcnt with dichloroisoproterenol ( DCI ) , a

heta-adrciicrgic Mocker, cpincplirint~ and norepincphrint. not od\. prodiiccd arousal in UU the aiiinds, Iiiit an arousal of l~olongetl duration. 3. The alpha-adrenergic blockers, chlorproinazine, phenoxybenzamine, and dibenzyline, suppressed the stimulant action of catccholarnines, whether in tlic 20% spontaneous group or following trcatmcnt u i t h DCI. Howevc-r, other blocking agents, such as azapc’tinc, dihydroergotaininc, iuid plitntolainine, failed to inhibit thcx central effects of catecholaniines, even a t doses that did inhibit the peripheral effects of catecliolamiiies. 4. lsoproterenol exerted an EEC; stimulant effect which could be blocked by DCI and by all thc alpha-adrenergic blockers. Following such a block of either alplia- or beta-adrenergic receptors, the effcct of isoproterenol was iiow oiic of sedation. A later study (Goldstein, 1962), showed that LSll ($5to 100 &kg, iv) also blocked the EEG effects of isoprotercwol, in a manner similar to the action of ] X I . On the other Iiaird, its nonhallncinogenic analog, 2-l)roni LSU, produced no blocking cffect even at very high doses. 5. Epincyhrine, but not irorcpirieplirine, evoked an EEG pattcni of Iiypcrsyiiclironizatioii whcm adiniriistered after injection of alplia-l,locl\iiig agents ( characterizcd by their ability to supprtxs the stimulant activity of catecholamil ) . Anothcr condition under which cyinephrine displays a scdativc rather than stimulant effec,t w a s drwril~cdby Drohocki et (12. ( 1056~ ) . The degrcc of scdatioir in rabbits anesthetized with ethyl carlxiinate was increased fol1ov.on of epinephrine. sed and/or prcwwtecl tlic. EEG sedative effects of a varic2ty of agents apparc.ntly iinre1atc.d to the adrenergic system, such as pentobarbital, niorphincs, and nirprobamatc:. I t was ineffectivc against EEG hypersynchronization induced by chlorpromazinr~ or 1~hc.iiozybenzarnine( Goldstc,in rt ul., 1961). 7. The universal stiniiilant cxffects of amphetamine were suppressed b y the same agents which were found to be effective against cat ccholamines. 8. The specificity of the aforc31nc1itioned reactions was emphasized by the inability of eithw alpha- or beta-blocking agellts (or the simultaneous injection o l hoth ) to affect the EEG stilnulant properties of caffeine or pei7tylc.lic,tc’tl-~~~~I[,. These studies, based on statistical criteria of sigliificallce in relation to changing MEC l c ~ ~ ~ (lcorrwponcliiig c. to changing seda-

tion-arousal states), niay be interpreted as evidence for the existence of two adrenergic pathways in the central iicrvous system: one related to the alpha receptors and involved in aroiisal phenoinena, and the other related to the beta rcceptors, intervcning in sedation phenomena. HS L \ s D

~11S.rAhIIZE

As mentioned in the section on histamine, this naturally occurring amine typically exerts an EEG stimulsnt effect. An indirect inechanisin of action, involving release of stimulant cat echolamines by histarninc, has h c w i frequently considered. Ho\vever, sucli a mechanism has lieen refuted by Goldstein et nl. (1964b) i n a study of animals pretreated with chlorpromazine; the latter tlrng had no cffcct on the EEG stiniulant properties of histarninc. On the other hand, prctreatnient with l~romethazine, a centrally acting antihistaminic agent, did abolish the stimulant effect of histamine.

E.

r \ ~ ~ ~ O P I ~ E - ~ I I O L I N E RAGNIDC h R X K E R C : I C

DRuc:s

I n rabbits, Goldstein (196011) studicd the effect of atropine on the central action of deanol, a choline precursor which (as previously mentioncd) doc,s influence brain activity. In animals displaying EEG ~iypersynclironizationfollouing pretreatment with deanol!, atropine (1 mg/kg, iv) caused an iinniediatc revcrsal of the lattc'r sedation pattern to one of alertness; the cff ect was quantitatively indicated in the integratcd I wording h y a return to control hlEC lcvc~ls.This alert state persistctd for 12 to 15 minutcs, after which hypersynclironization resumcd. Atropine ( 1 tng/kg) dorw induces a 1iyPcrsyiichronized pattern charactcrized by a shift in tlie st;ctisti:.al distribution of energy measurements to a higher level without change in the fiducial limits; in contrast, clranol-indncc,cl hypersynchronizatioii produces a marked widening of the distribution curve. It seemed of interest to dctcrmine whether the EEG sedation following atropine reversal ( arousal ) of the tleanol hypersynchronization was due to resumption of deanol activity or due to an additional atropine effect delayed by the presence of deanol. The problem was resolved by identifying the nature of the distribution curve of measiirenients for thc sedation period in question. It proved to be a tleano'l-typ distribution, implying resiunption of deanol activity.

;In iiiteractiori of choline a i i d dtaiiol was also reported in this study. Pretrc~~tiiiciit oi rabbits with clroline inore than doubled the tinic (latent pcriod) necessary for doanol to reach the peak of its hy1)trsyneliroiiization effect. Another csaiiiple of atropinc interaction coiiceriitd its tendency at \ - c ~ ylo\\, doses (5-10 ,,,g/kg) to iiicluce E E G arousal in coinparisoii to tlic Iiyl~~~rsyiicIaroiii~~ltioir typically effected by larger c1osc.s ( 1 nig/kg). Pretrcatnicnt of tlw rabbits \ ~ i t hclilorproinazinc (1 mg/l\g, iv) completely a1)olished tlic, arousal effect (Beck and Golclstcin, 1964 ) . This jvas vic,\vcd as a 1)ossible indication that thr EEG arousal of very low c1osc.s of atropiiic vwi due to an indirect releasti of catccholainine. Grcwlljcrg ( t (iZ. (1961) s t i i t l i c d t h ( s effect of various stiiiiulant agents on rahhits trcatcd \\.it11 c~tlranolat ;I dose maintaining a blood level of 300 ing X . This conccmtratioii of cthanol produced an EEG pattern of’ deep sedation with a conc.oinitant high in MEC. Amphetamine ( 5 mg/l\g, iv 1, deanol ( 100 nig/lcg, i v ) , carnitinc (100 nig/kg, i v ) , and LSII (5 pg/kg, i v ) reverted the hy1)ersyneIironous activity to :ii~Pro~iiii;it(’I).. prc~-cthanol levels. Under these conditions, EEG aroiisal did not necessarily correspond to bchavioral arousal, although thc a p p i r m t dissociation \\‘as difficult to cbvalriate in tlic rclativc~lycwrstlaiiicd animals. G. H\i13O\’OLEhilC ~ l \ i I ~ ~ CA\(;LIOSIC 1JLoc:I;ms

I ~ ~ : S S I o ~ - . ~ \ I ) AI S~DI ~ i ~ : ~ ~ ( ~ I ~ ~

:is inc~iitioncdprwiously, lrypovol~michypotension, induced in rabbits 1)y draining a volume of blood corresponding to 1%body \wight, cffclcted an EEG pattern of sedation, with a large increase in MEC. Coldstcin and Xluiioz ( 1961a ) p(~forinedsuch expcriments in animals prctreated with various agcwts to deterininc wliethc,r the EEG effect \vas due directly to a cliairgo iir ldood mass, or indirectly due to thc physiological effects of I)lrcding on altrriiatc CNS pathways. Plienosyl>cnzamine ( 1-5 nig/kg, ik.), an alpha-adrenergic blocking agent suppressing the arousal effwt of catecholamines, did not prevent an increase in MEC following hlmding. Phentolamine ( 510 ing/kg), also an alpha-adrcmrgic blocker (which does not,

304

LEONIDE GOLDS‘IEIS 1SD RhP?rIO.\D A . BECK

however, affect the EEG stimulant action of catecholamines) significantly reduced thc scdation due to hypovoleinic hypotension. Similar interaction was demonstrated with DCI ( a beta-adrenergic blocker) and ~ i t hamphetamine. II~wmc ~thonium ( 0.1-1.0 mg/kg, iv) had an inverse eff vct in deepening the level of postbleeding sedation. XIV. Miscellaneous Drug and Placebo Effects

A.

CUlWRE

Although it is gent,rally believed that d-tubocurarine does not cross the blood-brain liarrier, and so exerts its apparent central cBects indirectly, Drohocki and Goldstein ( 1956b) analyzed the EEG’s of rabbits unde.r sub1iaralytic doses ( 50-200 +g/kg), ~ h i c h induced relaxation of only the neck and ear muscles. They found that althoiigh the MEC did not differ significantly in the pre- and posttreatment rccordings, thc shape of the statistical distribution of rncasurenients w a s indeed affected b y the drug. In pl;tce of a sharply defincd peak for the class corrcspoiiding to the mean, there occurred at least two a:djoining classcs with idcntical freqncncy of occurrence'.

B. PcKIPL1’ 4

RAZOLE

This coiiviilsant agcmt \ w s stridicd by Drohocki and (-;oldstc$n (1956a) in that it afforded an opportunity t o analyzc thc shifts in three apparently continuous, overlapping states of the ccliltral nervous system, namcJy, wakefulness, excitation, and coiivulsions. Following administration of progressively increasing doses of pentylenctc,trazolc, EEG mc~asurementswere' inade for very short time intervals, most often of I-second duration. Ten a n d 30 ing/kg, iv, cffccted a significant decrease in both tlie mean numher of pulses per unit tiinc. and a dwreasc in thc variability. \Vitli doses of 40 nig/kg, iv, the decrease in both parameters \\as still initially evident but then w a s overshadowed in 20 to 30 seconds b y a large increase in energy content associated with the appearance of convulsive activity. In decided contrast to other kiio~vn states of increased MEC, the variability of the EEC: diiring convulsions w a s almost zero. A search for p0s:iibIe continmim or developing trend within the MEC levels iinrnecliately preceding the convnlsive phenomena w a s inconclrisive. That is, the shift n 7 a s so rapid as to o1,scm.e the

possiblcl existence of an e n c ~ g ystat(- iiitcrmcdiate between mere excitation and drug convulsioii. Iliis tiirniiig point, lwtween a sharply delimited pattcrii of tlc~crcxscd IIEC and an abruptly appearing pattern of incrcased RIEC, actiially suggested two individual EEG’s rather tlian thc EEC; of on(: animal.

c. 1-’r,:\ceuo :Is has been frequcmtly o l ) s c w c ~ l ,tlw cbffctts of pharmacologically active drugs (such as stiinrilants. scdatives, antianxiety ageiits) niay oftcii be convincingly rcylicated on surrcptitioiis siilxtitiition of the active agent by a ~~liariiiacolo~ically inert c o m ~ ~ o ~ ior nd placebo (such as lactose or starch ). Tllcrefore, in all qiiantitatcd EEG drug studies performed on human subjects ( a t least in the LTnitcxcl States), admiiiistratioti of placc4)o was includcd. A "triple1)lind” design was routinely applicd. so that neither siibjtbct iior mcdical invcstigator nor t h . tcx,hnic.iaii analyzing EEG records \\7as iiiformrd as to tlw n a t i i u - ot t h c ~ agent ( driig or placebo) adininistc.rcd i n a particiilar stiitly. Iiivcstigations of placebo c,ff-‘czcts\\‘CT(, corrductcd by Goldstein ct a!. ( 1963a), Rfurphrce et nl. ( 1961), Pfcifter et (11. ( 1963), and Pfeiffer (1965). In most sul)jc ’, placc-110 produced no significant change in either the XlEC or t C17.However, in a f c ~ vvolunteers, the EEC: did reveal significant t1c.crr.a or increases in the MEC (as comparcd to preplacebo control 1t.vc.l~) , with or without associated changes in the C\’, Such chaiigc~were dctcctablc in EEG sainples tnkcn at various tiines during the usiial 6-hour period of recording. 111contrast to the, EEG cifcbcts of active drugs, placebo effects on the MEC or C\’ seem totdly unrelated. For example, a d c w e a s c d MEC ant1 iiicrc~iscdCV itlviitifird 2, hours aft(-r placebo, inay wcll revc’rse to an incrcmcd X I ISC a i i d tltwcascd C A T 1 hour later. Furthcmiore, the aforc~iiic~iitioiic~tl KEG changes have 1)ecn s1ion.n to be randomly distrilnitcd; tliat is, in a n y single group of at lmst S to 10 volunteers, statistical aiialysis of tlie total EEC; data, incliiding that obtained from placc,l)o-rc.~ictiii~ subjects as wcll as from nonreactors, reveals no signific~aiic.~ in tlie variations of the 15EG parameters considered. XV. Discussion and Conclusions

T h c . v a l w o f thc data ol)tait i c ~ l\\.it11 the integrative method of KEG aiinlysis is ptdiaps lwst j i i d q d I)!, a i i m iiig a sirnple thoiigh

306

LEONIDE GOLDSTEIN AND RAYhfOSD -4. BECK

highly relevant question: Does such quantitated data provide more information, or a difererzt kind of information, than that derived from visual inspection of EEG records alone? Indeed, this would aplwar to be the most (critical, if not the only, question to be raised in the present stage o:t‘ development of electroencephalography as applied to neurophysiology aud ncuropliarniacology. That is, in any purportedly quantitative investigation of biological phenomena, popular critcria of scientific soundness, such a s “precision” or “accuracy” or “dynamic range response’ are poorly applicable if not invalid. As emphasized in this review, the direct, intrinsic source of the electroencephalogram is as yet unknown, so that the precise relationship of EEG measurements to the true statc of brain function remains undcfined. It is for this reason that the most acceptable criteria currently employed in this field are those of reproducibility and statistical validation. The application of statistical methodology to measurement of bioelectrical phenomena has thus far been restricted to direct “utilitarian” testing of thc. significance of changes in states; and such tests are indeed applied to thc integrative method. In addition, however, statistical analysis of quantitated electrogenesis may well serve to characterize :a bioelcctrical state in terms of the interrelationship of a poplatioil of cvents comprising this state. For example, such an interrelationship may be estimated by the variability of the EEG, a parameter, though often neglected, potentially suitable as an indicator inore sensitive to change in functional states than reflected by actual levels of over-all activity. Thus, in summary, data obtained from the quantitative integration of the EEG under varied cxperimental conditions have revealed the following hcrcltoforc. unknown or even unsuspectcd findings:

1. A difference 111 thc levc.1 of brain wave variability in normal subjects as compared t o male chronic schizophrmic patielits 2. A correlation h t w e e n thr level of EEG aniplitncle variability and psychological I~ehavioralratings of chronic schizophrcnics; 3. A decrease in EEC. variability, indiiced b y CNS stimulants and hallucinogens in normal subjects, to ‘1 level approacliing that typical of the untreated schimphrenic 4. A concept, derived from aninial studies, that stirnitlation is ;I graded rather than a n “all-oi-none” phenomenon 5. A n incroaw in thc I X G ~ a r i a l ~ i l i t(dmpitc y a decre,tw in the

ovcr-all EEG amplitude) of normal subjects treated with antianxiety agents 6. An aritliinetic typc progrcwioii in the increased level of MEC in animals trcated with aiitiaiisic~tytlrugs. c i . .I gcwinvtric type prognwioii ill tlic MEC changes preceding slecy itr irormal voltintcxc'rs trt,atotl with pentobarbital. 8. A difkrcnce in thc slopt~ of the evolution of the MEC, as well as in the level of the platcau attained, following administration of pcntolxirliital to norinxl su1)jccts and to chronic schizophrenics 9. An indication that pattcmis such as hypersynchronization can correspond to cliff rreiit specific distributions of the values of the elrctrical viiergy levels around their iiicans 10. A practical, reproducible method for evaluating chemical agciits in respect to such spccific factors as onset, peak, and duration of pharmacological action, as \r~.llas determination of tlieir relative potcncies 11. More generally, an instriunc~iit to define the bioclectrical events corresponding to a gi\xm lwha\,ioral state, e.g., by the limits of distribution of nieasuremmts ol)tnined during its occiirrmce; from siich a definition, the possi1)ility to ascertain statistically not only the significance of a chaiigc, h i t also the characteristics of the state evolved by such changc.. ( S(Y Table I11 for a summary of EEG data obtained in human sribj(,cts.) On the basis of these obscrvatioirs one may conclude that the integrative method of EEG analysis pi.ovides both more information and also a tliffcrcnt kind of information than that derived from visual inspcction of EEG recortls alonc. Assuming that intcgratcd 1CFX data reflccts the action of physiological mechanisms of the braiii to n reasonable extent, one could cautiously propose a model of h a i n function derived from such data. Such a model suggests itself in the symmetrical spread of bioelectrical values around thcbir respective means, and in tlic change of spread of such a distrilmtion in relation to varying states, such as arousal or sedation. I I I other words it suggests a homcostatic model. This model of brain fiinctioii ( a t cortical levels) is essentially characterized by the regulating mcchanisms maintaining a state of equilibrium in a constantly chaiiging cmvironment. Stimulation, hypercxcitation, and hallucinatory statcs (spontaneous or drug induced ) would correspond to difl'twnt drgrccs of hi/i'ci,-regulation.

'I'hc clriig valiies listcd correspond i o iii:tsirii;il efi'ect,. of siihjcct,s involved in each stiidy. 'The iiiiniber of iiidividud iiieasrirrinerits from wliicli the iiieaii energy content (AIlN'j :tiid codficient of variation ( C W ) were cstirnnt'ecl w:is most oftcii 50; for t~xniiiple,3 9 0 iiiea,siirmieiits were iised for the calcrdatioii c ~ fthe levels of the 1lPK' xiid C'V in normals iiiider LSD. c The l l E ( ' bvvas tietcwniried by ti:tnsforrii:~tic)iiof direcnt iiitcgrntor data from calihratiori characteristics oxistciit iiiiiiietliatc~ly before the rwordirig of each

* Number

espt?rinieiit,.

In contrast, drowsiness, sedation, and drug-induced sleep would imply hypo-regulation. Normal \vakefuhiess, then, would be considered an optiinal level of regulating nieclianisms functioning in an intermediate position bctween mechanisms prevailing during excitation and those prevailing during sedation. At first sight, such a model might sc'em to contradict tlie obscrvation that behavior during excitation or in schizophrenia is decidedly more variable than normal. However, it is to be understood that hyper-regulation corrcsponds to loss of function. Theoretically, the extent and precision of responsiveness in a homeostat is directly

AMPLITUDE ANALYSIS OF THE EEG

309

related to the variety of its reactive units (Ashby, 1958). Therefore, the correlation of decreased EEG variability with hyper-regulation of brain mechanisms is not, in effect, contradictory to increased behavioral variability. It is quite apparent that the aforementioned considerations involve theoretical constructs without much factual basis. It must also be stressed that the integrative method of EEG analysis reveals merely a small chapter of the electrophysiology of brain function. This type of analysis is obviously restricted in that it applies to only one aspect of the EEG, neglecting such parameters as frequencies, phase relationships, and waveform correlations. However, despite its limitations, it does indeed have value as a practical tool for exploring an intriguing feature of what is perhaps nature’s most fascinating achievement-the brain. ACKNOWLEDGMENTS

We express a particular debt of gratitude to Dr. Zenon Drohocki, the late Dr. Bruno Minz, Dr. Carl C. Pfeiffer, Dr. Harry L. Williams, Dr. James A . Bain, Dr. Henry B. Murphree, Dr. A. Arthur Sugerman, and Miss Elizabeth H. Jenney. The able assistance of hlmes. Diane Leibach, Jenney Stephan, and Martha Hopkins is gratefully acknowledged. The work done in the U. S. A. was supported in part by grants from the Geschickter Fund for Medical Research and the American Medical Association Education and Research Founclation.

REFERENCES And&, J. ( 1945). “Thesis in Medicine.” C . Thomas, Nancy, France. Ashby, W . R (1958). Cybernetica 1, 83. Beck, R. A. ( 1965). Unpublished observation. Beck, R. A,, and Goldstein, L. (1964). Federation ProC. 23, 561. Beck, R. A., Goldstein, L., ancl Pfeiffer, C. C. (1963). Pharmacologist 5, 238. Beck, R. A., Pfeiffer, C. C., and Colclstein, L. (1964). Pharmacologist 6, 204. Berger, H. (1929). Arch. Psychkit. Neruenkrankh. 87, 527. Berger, H. (1938). Nouu Acta Leolmlrlina F, 6. Bradley, P. B., and Ekes, J. (1955). Brain 80, 77. Bruck, M. A. ( 1960). Electroencephalog. Clin. Neurophysiol. 12, 528. Dement, W., and Kleitmen, N. ( 1957). Electroencephalog. Clin. Neurophysiol. 9, 673-690. Domino, E. F., and Hudson, R. D. (1959). J. Pharmacol. Exptl. Therap. 127, 305. Drohocki, Z. (1937). Arch. Ges. Physiol. 239, 658. Drohocki, Z. (1947). Ann& Psychol. 47-48, 230. Drohocki, Z. (1948). Rev. Neurol. 80, 619.

310

IXONIDE GOLDSIEIN AND HAYSIOhD A. BECK

Drohocki, Z. (1954a). Reu. Nettrol. 91, 304. Drohocki, Z. (1954b). Rec. N c n d 91, 305. . Nertrol. 91, 305. Droliocki, Z. ( 1 9 5 4 ~ ) Rev. Drohocki, Z. (1954d). Rev. Nezirol. 91, 306. Drohocki, Z. (1956). Rev. Neurol. 94, 804. Drohocki, Z. (1957a). Rcu. Nezrrol. 96, 475. Drohocki, Z. (1957b). Rca. Nerrrol. 9G, 516. Drohocki, 2. ( 1 9 5 7 ~ ) .French p;itetit issucil to tlic Centre National de la Recherche Scientifique. Drohocki, Z. (1960a). J. I’h/siol. ( P a r i s ) 52, 83. Di-ohocki, 2. (196Ob). Rev. Ncrrrol. 102, 320. Drohocki, Z. ( 1 9 6 0 ~ )Reu. . Ncrrrol. 103, 270. Drohocki, Z. (1962a). Reu. Nczirol. 107, 204. Drohocki, Z. (186213). Rev. Neurol. 107, 211. Drohocki, Z. ( 1 9 6 2 ~ ) R. w . Nerrrol. 107, 257. Drohocki, Z., and Duflo, G. ( 1958). J. Physiol. (Pnris) 50, 251. Drohocki, Z., m d D~iflo,(3. (1959). Reu. Wcttrol. 100, 330. Drohocki, Z., ;ind Goltlstciii, I,. (195Ba). Rcv. N e f t r o l . 94, 901. Drohocki, Z., and Coldsteiri, L. (195Bb). Rcw. Ncnrol. 94, 904. I3rohocki, Z., and Goldstcin, L. ( 1957). Arch. Sc,i. I’hysiol. 12, 59. Drohocki, Z., and Soussen, 6. ( 1%59),Rev. Ncrtrol. 100, 3%. Drohocki, Z., Goldstein, I,,, and Him, 13. ( 1955). Compt. Rend. Soc. Biol. 149, 2115. Drohocki, Z., Goldstein, I,., and hfinz, B . ( 1 9 5 0 ~ ) Rcr;. . Nettrol. 94, 141. Drohocki, Z., Goldstein, I.., and hlinz, B. (1956b). Rev. Neurol. 94, 144. Drohocki, Z., Goldstein, L., and Slinz, 13. ( 1 9 5 6 ~ )Rcu. . Nctcrol. 94, 145. Fisher, R. A. ( 1830). “The Gerietical Thcory cd Xiitmid Selec,tiori.” Oxford Univ. Press, London and S c \ y York. F r a m , D. I-I., and Green, J. P. ( 1963). P7i(irtti(Ic.o106i.,t 5, 253. (;iIibs, F. A., a n d Gibbs, E. L. ( 1952). “Atlas of Electroer1c~~pl1~1lr,yr3l,hy.” Addison-Wesley, Reading, Massachusetts. Coldman, D. (1962). Ann. N . Y. Accitl. Sci. 96, 33i. Coldstein, L. (190Oa). Federntion Proc. 19, 291. Goldstein, L. (1960b). 1. I’hnrmacol. Exptl. Therci?~.128, 392. Goldstein, L. (1962). Federation Proc. 21, 337. 130, 204. Coldstein, L., and Aldunate, J. ( 1 9 G O ) . J. Phariiwcol. E.xptl. Tlicrc~p~. Goldstein, L., and Minz, B. (1955). J. Physiol. (Pari.s) 47, 591. Goldstein, I,., and Muiioz, 13. (1960). Pknrrnacologht 2, 80. Goldstein, L., and Muiioz, C. (1961a). Acta Phgsiol. Ltrfilioarrl. 11, 239. Coldstein, L., and hfuiioz, (2. (1961b). J. Pharnincol. E x ~ ~ tTl h. c r o / ~ 132, . 345. Goldstein, L., hluiioz, C., and Norton, G. ( 1961 ) . ISlcctroence)J/iu/og. Chi. hleitrophysiol. 13, 167. Goldstein, L., Jenney, E. II., hfurphrec, €1. B., m t l Pfpiffcr, C. C. (1962). Proc. Intern. Union Pliysiol. Sci. 2, 1219. Goldstein, L., Murphrco, H. R . , Sugcrman, A. A., Pfeiffcr, C. C., and Jenney, E. €1. ( 1963a). Clitz. I’harinncol. Theraf). 4, 10. Coldstc.iii, L., Murphrce, H. B., and Pfciffer, C. C. (19G3h). Ann. A‘. Y. Acnd. Sci. 107, 1045.

Goldstein, L., l’feiffer, C. C., antl hluiioz, G . ( 1 9 6 3 ~ ) I.‘edcrcttion . Proc. 22, 424. Coldstcin, L., Pfciffer, C. C., Murpliree, H, B., and Jenney, E. 11. (1963~1). Phurinucologist 5, 233. Colclstciii, L., Stolbcrg, H., and Srigcrman, A. A. ( 1964a). l S t h Meeting Am. Electrocriccplaalog. Soc., Siinta F’e, N I w Mexico p. 108. (;oldstcin, I.., I’fciNcr, C:. C., hlnfio;l, C. ( lR64h). Fec/o.c/tion Proc. 23, 1113. Goldstein, Id,,Nelson, S. D., and Ilciilcy, K , (1965). Fcdcration Proc. 24, 52. Cr(wil>erg, R. E., (:oltl.;tcin, L.,ancl l’lc~illt,r, (:, C. ( 1964). P/iur.i,icicologi.,t 0, 170. (:roth, D. l]., Uniii, J. A., a n d Pfc>iflvr, C. C . ( 1 9 5 8 ). J. Pharnurcol. Exptl. Therap. 124, 290. IT;tlclane, J. B. S. ( 1932) . “Tlrc. Ciust’s of Evolution.” Harper, London, England. IIopf, M. A., Gnlletti, l’., and Coltlslcin, I , . ( 1961). Proc. Am. Soc. Artifcictl lntertrcil Orgcins 7, 231. Jenney, E. II., hlurphree, €1. B., C:ciltlstciii. I,., and Pfciffer, C. C. (1962). Phorn1acologi.ct 4, Ifxi. Kornmullc~r, A. E. ( 1987). “Die I,itrc.l(.l\tris(.lic.n Erscheinungen cler I-Iirnrindfeldor.” lliiemc, Leiprig, iiliin).. Knoll, J., and Koinlos, E. (1951). ri(,!i~Z’llysiul. Acad. Sei. l l u n g . 2, 57. Idongo, V. G. ( 1956). J. Pllciritutcv/. K x j ) f l . Thc~rcip.11F, 198. hlulioz, C., and Goldstein, L. ( l!)fiO), l’/iri,tttttc,ologist 2, 80. hluiioy, C.,antl Coklstcin, I,. ( 186ln) . / 2 c / r i l’/iy,~io~. Lulinocirn. 11, 242. \luiioz, C., i i i i d (hldstein, I,. ( lU(ill)).1. I ’ l i r r r i t i t t c ~ o 2 . Exptl. Tlicrap. 132, 354. \lurplirc.c’, IT. 13., (;oldstein, L., l’fc~iflc~r,(:. (;., a i i d J ~ ~ i c E. ~ y 11. , ( 1962a). I’lurrn7cic.olo6.iJt 4, lMi. hlrirphrce, 11. n., Jcww),, E. II., ; i i i t l I’1c~ifl(~r. (:. C . ( 1962Ij). Fcdcratiuti Proc. 21, 337. Jlriqdirc~e,11. U., Sugcrmnn, A. .4., J I Y I I I < > ! . . 11. I I . , ;inti Schriltz, R. E. (1963). FerZcr(ition Pro(:. 22, 510. hfru-plir(’e, IT. n., Coltlstriir, I,., I ’ i c ~ i l l ( ~ r(:, , (;., Schranini, I,. P., ancl Jenney, E . 1 1 . ( 1064). Itltet’li. 1. ~ ~ ~ l ~ ~ ~ J ) J / i t / l l:j,l l 97. t i l ~ ~ ~ / . Pfeiffer, C. C. (1965). J. New Drrig.s 4, 209. Pfciffcl-, C. C., antl Goldstch, 1 , . ( 1964 ) . J . rirop.s!/cltic/t. 5, 475, I’fciffer, C. C., kind Schnltz, R . b;. ( 1 U(i4). l;., ?rlurphrc,c, 11. I < . , and Jenney, E , 11. ( 1964a). Arcli. Gcti. Psychint. 10, 446. PfeiEcr, C. C., Goldstein, L., h l i i r p h w c , 11. H., a n d Jenney, E. 1 1 . ( 19641)). ~ c f i r o ) ~ , s y c ~ a o ) ~ h a r m3,a c4G6. o~. Pfeiffer, C. C., Goldstein, L., Kelson, S. D.. 13eck, R. A,, and Mlurphrcc,, €1. B ( 1965). Proc. 13th Ititern. Congr. Plz!/.sii~l.T o k y o , Japnii. Picri-e, R . (1957). C o i i ~ p t .Rcrd. S O C . R i d . 151, 698. ) . Ant. J. Mcd. 14, 456. Scevcvy hf. I T . , and \Voods, L. .4, ( 1

312

1,EONIDE GOLDSTEIN Ah11 HAYXIOAD 4. BECK

Soussen, G., and Clinssaing, €1. ( 1960). Cercbral Anoxia and the Electrocncephdogram, Cob{. Rctcnion Enropc‘entu! Inform. El[’c/,.ocncel,hulofi., pp. 209-213. ( l‘honias, Springfield, Illinois.) Sugerman, A. A , , Goldstein, I,., hlurplirec, H. B., Pfeill’er, C. C., arld Jeiiilcy, E. I t . ( 1984). Arch. G i n . Ps!/chicit. 10, 340. Szerb, J . C. (1957). Arch. I r t l w n . P/tarnrocodr~ir.61, 314. Wikler, A. (1952). Proc. !bc. Erptl. R i d . 79, 261 Wright, S. ( 1940). In “ ‘ I h i : N e w Systematics” ( J . IIusley, c ~ t l . ) ,pp. 181-183. Oxford Univ. Press, London and New York.

AUTHOR INDEX N u i n l m s in italics refer to page\ listed.

A .4brcu, 13. E., 228, 263 Aht, J. P., 16‘2, 191 Atlcy, W. R., 24, 25, 28, 27, 30, 77. 79, 81, 84, 85, 88, 80, 90, 121. 132, 135 Atlriaii, E. D., 109, 133 i\garioal, 1’. S., 203, 216 Aitkeii, J. T., 43, 69 Ajiiione-Xlnrsnn, C., 63, 72 Akcrt, K., 79, 114, 136 A h - F e s s a r d , D., 43, 56, 57, 59, 60, 61. 62, 63, 6‘6, 67, 68, 69, 69, 70, 72, 7.3 All)crt, K., 144, 191 Altliinatc~, J., 299, 310 Alcuandcr, F., 204, 211, 219 Alcxaiidvr, I. E., 146, 191 Alpern, E. B., 149, 191 Alpcm, H., 162, 192 Altiiian, J., 47, 70 Alvord, E. C., 14, 17, 30, 34 Amawian, \’. E., 25, 30, 46, (31: 70 Ainin, A . I I . , 207, 216 Andersen, P.,26, 30, 84, 88, 89, 125 132 Anderson, F. D., 48, 49, 56, 57, 59. 70 Andcrson, J. A , , 203, 216 Anderson, S. A . , 49, 50, Fjl, 52, 61. 67, 70, 71 Aiidi-6, J., 272, 309 Andy, 0. J., 7, 8, 13, 20, 27, 30. XI, 85, 132 Angaut, P., Fj9, 62, 68, 70 Aiigelcri, I?., 49, 50, 73, 83, 1.3.3 Aiigc~Tiiie, J. E., 13, 17, 20, 27, 28,

oil

\.rliich thl: complcte refflrences :ire

Armt i t i \ , J. C., 6, 30 Ar(111iiii. .4., 78, 79, 85, 88, $10, W,

103, 105, 106, 107,122, 132, 1.35 XI. C., 82, 104, 132 AriAis K a p p c w , C. U., 8, 9, 17, 20, 84, 28, 30, 55, 58, 70, 88, 132 Aririitngc~,S. G., 147, 148, 191 Ariiistroiig, hf. D., 198, 109, 204, 216 Arlloltl, F., 6, 8, 30 Aroiisoil, H., 208, 2 l S h r t l l u l , It, l’,, :39, 70 A h l ) ) . . If’, H., 309, 309 .4stiii. A . \I’., 1.44, 191 Aiild, R. M.,198, 199, 218 Avtxs, E. K., 203, 210 Axt~lrtrd, 210, 216 Aytl, P’. J,, Jr., 208, 216 ‘Ar(Iiiii1i.

B Unilc.y, C. J., 156, 195 BniltAy, P., 10, 20, 22, 33 B;iil(,y, 11. A., 51, 72 I h i i i , J . A , , 285, 311 U i t i t ( x r j w , S., 203, 216 naiin, ‘Y.E., 252, 262 U;lrbeaii, A,, 202, 216 Bt~rd,P., 88, 132 nnrgman, w., 28, 30 U x i - o i i , 11. N., 200, 216 B a ~ i t t l ( ~ S. s , H., 166, 191 Ihrrc,tt: 11. E., 148, 192

I 3 a x 1 , J. A,, 208, 216, 3 1 R H c , a r n , A. G., 201, 216 Bvtiulcy, R. hl., 46, 73

l h ~ k H. , A,, 284, 285, 286, 288, 290. 291, 295, 303, 309, 311

314

AUTIIOR INDEX

Btguin, M., 228, 261 Bennett, E. L., 155, 158, 159, 187, 191, 191, 195 Ikesford, \V. A., 51, 70 Berger, H., 266, 272, 309 Bergsnian, A,, 205, 216 Berlet, H. H., 204, 206, 210, 212, 216 Bcrnharclt, K. S., 140, 191 Bernsohn, J., 203, 208, 218 Bcrry, C. hl., 49, 56, 57, :TO Bertino, J., 208, 218 Bessman, S. P., 198, 199, 219 Rialy, 11. S., 256, 263 Bickel, II., 199, 216 Biehl, J. P., 213, 216 Bicl, W.C . , 143, 157, 191 Bignami, G., 173, 192 Bishop, G. H., 39, 42, 70, 82, 132 Bishop, M. P., 252, 261 Black, A. I I . , 150, 151, 191 Blackstad, T., 22, 25, 31 Blodgett, H. C., 141, 192 Bloom, W., 172, 194 Bobon, J., 252, 261 Bogdanski, D., 207, 218 Bogdanski, D. IT., 125, 126, 132, 138, 208, 216, 218 Rohdanecky, Z.. 95, OR, 1351, 133, 159, 186, 192 Boldrey, E. B., 67, 7 4 Bolles, R., 142, 182, 195 Bonewell, C. W., 190, I96 Bonnet, V., 94, 133 Bonvallet, hl., 99, 111, 235 Borck, E., 199, 216 Borensteiii, P., 62, 70 Bossier, J. It., 228, 261 Boszornienyi, Z.,209, 216 Boughton, J2. I,., 146, 192 Hovrt, I)., 79, 80, 111, 117, 136, 155. 171, 173, 178, 179, 192, 194, 195 Botvslior, D., 41, 43, 45, 4 6 , 47, 48, 49, 50, 51, 56, 57, 59, 64, 65, 66, 68, 69, 69, 70, 71 Boyajy, L. D., 99, 138 Boyd, J. D., 14, 19, 31 Brack, A., 209, 218

Bradford, I)., 188, lY5 Bradley, P. B., 80, 89, 9.1, 95, 99, 100, 103, 105, 106, 121, 123, 133, 267, 309 Brazier, M. A. B., 89, 134 Brechcr, A,, 199, 216 Breen, H. A,, 184, 192 Bremer, F., 190, 192 Bridger, J. E., 43, 69 Bridgman, P. W.,141, 192 Briggs, M. H., 190, 191, 192 Brinley, F. J., Jr., 85, 91, .I35 Broca, P., 2, 31 Brodal, A . , 27, 43, 53, 56, 57, 66, 70, 74. 77, 133 Brodie, B. B., 207, 216, 218, 219 Brooks, D. C., 106, 133 Brown, 13. H,, 209, 217 Brown, C. \V., 148, 192 Brown, F. C., 205, 217 Brown, H. O., 150, 196 Brown, J. R,,65, 70 Brown, R. H., 204, 212, 214, 218 Bruck, M. ,I.,272, 309 Briicke, F., 85, 88, 90, 91, 96, 98, 101, 102, 103, 106. 111, 123, 124, 133 Bruland, H., 26, 30, 88, 89, 132 Brune, G. G., 199, 203, 204, 206, 208, 210, 211, 217, 219 Bruner, J., 61, 70 Bull, C . , 204, 206, 210, 212, 216 Bumpus, F. hl., 204, 217 Buniatian, 13. C . , 256, 261 Burex, J., 95, 133, 159, 164. 186, 192 Burezod, (I., 159, 164, 186, 192 Burgen, A. S. V., 08, 13.3 Burr, H. S., 15, 31 Burt, G., L57, 178, 179, 1 9 4 Buscaino, G. 4.,203, 217 Buser, P., 61, 62, 70 Buzzard, E. F., 43, 71

C Cadilhac, J., 79, 89, 90, 121, 122, 133, 136, 137 Cajal, S. R. Y., 41, 63, 71, 77, 84. 88, 1.33

C:IIIi(>liii. \V. H.,Jr.. 153, 176, 185, lM, 189, 192, 196 Caiib,.&, Ll. J., 210, 217 Cardo, B . , 186, 192 Cardon, 11'. 1'. V.,208, 210, 218 Cnrlhon. N. J,, 150, 191 Carlswii, A , , 228, 2Fi7, 261 Carltoii, 1'. L., 153, 15.5, 131, lM), 19% Carman, J. B., 63, 71 Carpciitcr, D., 55, 71 Cnrpcmtcr, M. B., 47, 70 Cnrrcxras, hf., 50, 51, 52, 61, 67, 71, 85. 133

Ct.r(iuigliiii, S., 94, 133 in, T. J., 165, 187, 192 Cli;uitll(~r,R., 51, 71 Cluiig:, I I. T., 190, 1.92 Clrassniiig, H., 280, 312 Cliatoniwt, J., 94, 103, 133 Chipiiiaii, L. M.,98, 133 Chiroii, A . E., 121, 136 Cluiiouliovsky, M., 228, 2G1 Clitrkc, W.B., 64, 65, 71 Ck~ghorn,17. A,, 206, 217 C l t ~ l - J. , A . K., 43, 47, 71 Colcx, J. O., 24, 31, 140, 163, 194, 195 Collard, J., 252, 2F1 Collic,r. J., 43, 71 COllill.;, \\.. F., 36, 39, 69, 71 Coiiiiolly, C , J., 19, 31 Cook, E. I]., 202, 220 Cook, L., 140, 187, 192 Coons, E. E., 161, 192 Coopcr, R. XI., 145, 181, 192, 19.3 Corazz:~, R., 89, 133 Coi-coraii, A. C., 209, 219 Coriiing, 11'. C., 167, 192 Cost;,, E,, 123, 126, 127, 133, 137, 207, 208, 216, 217 C h \ i a n , hl. R., GO, 71 Cownn, I\'. hl., 26, 3.3, 63, 71 Cragg, n. C., 26, 3 1 , 88, 89, 13.1 Craig, J. XI., 201, 218 Crawford, Jl. A,, 200, 218

B. B., 207, 216 Crv\,c,liiig, C . H., 203, 220 Croiily-IXllon, J,, 54, $5 Crosby, E. C., 8, 9, 17, 20, 24, 28, 30, 31, 55, 58, 70, 88, 132 CiiII(,i-, I. 11. \I7., 26, 27, .31, 36. 57. 72 G1,rst.y, D., 214, 21s Ciit(,kiiiist, R., 163, 193 tmfF, \ I . A,, 88, 98, 134, 135 Gcrinaiiclt, 13. E., 115, 116, 1.37 Gcrrr, J . W.,214, 218 I~illiirPalasi, V., 203, 219 \'iltcr, R. \V., 213, 216 \'oelkcl, 4.,208, 219 \'ogt, \I., 97, 134, 207, 219

\ \ ' , l l l ) t ~ l g ,IT.,

46, 74

\\'alLe1, A . E., 1, 27, 33, 65, 66, 67,

74 ?\ all. 1'. D., 41, 48, 49, 50, 34, 55,

64, 75 \\

dIX,

I).,

99, 137

\\'~irtl,A. A., Jr., 25, 33. 175, 196 \ \ ' ; i r d t ~ i i , C.,

144, 191

\\ iisliizii, Y., 190, 19G

J. C., 256, 2G1 C. J., 213, 220 J . \V., 1, .31 \\';i!iitji., h l . J., Jr., 176, 178, 184, 195 \\'ea\Cr, L. c . , 228, 263 \\ c4,stc,r, K. E., 6.3, 7.5 \\ e t l t l t 4 , G., 38, 73, 7.5 \ \ eitliiimii, H . , 209, 210. -790 \\'c.il-hlallierbe, I { . , 200. 2-70 \\'eing:arten, hl., lS52, 174, 196 \\'ciss, 11. I]., 146, 19.5 , 'r., 79, 90, 05, $KJ, 107, 132, 1.7.3, 138, 159, 188, 192 \ \ ' t ~ i ~ h i c h I, I . , 12.5, 126, 132, 138, 20:3, 204, 208, 2Z6, 220 \\'cii(lt, R., 68, 72 \\'c~rnc~l, G., 111. 134 \\"woe, li'C., . 94, 10:3, 138 \\'vsthmok, \V. H., 157, 178, 179, 180, 181, 183, 183, 189, ZY1, 1 9 G \\'hd(m, R . E., 170, 1 9 3 U'hite, J . B., Jr., 205, 217 \l'liitc, J. C., 48, 75, 89, 1.34 \\'hitc., L. E., 14, 17, 22, 2,3, 24. 25, 26, 27, 30, 33, 34 \f'iitkiiis,

\Z,ttwii, \\'atts.

326

. ~ U ' I I I O H INDEX

\Vhite, K. P., 99, 103, 138 \Vhitehouse, J., 159, 196 \\'hitlock, 11. G., 27, 32, 33, 43, 45, 47, 48, 49, 50, 51, 52, 56, 58, 59, 67, 68, 74, 7 5 IVhitty, C. 117. hl., 24, 31 \Vickens, 11. D., 143, 157, 191 Wikler, A,, 103, 138, 267, 2'37, 312 Willianis, G., 146, 147, 148, 154, I96 \Villis, T., 3, 29, 34 Wilson, S. A. K., 201, 220 \Vitkovsky, P., 45, 46, 64, 72 \Voodcock, R. T., 99, 134 Woods, L. A., 299, 311 Woody, N. C., 201, 220 Woolf, L. I., 199, 801, 218, 220 Woolley, D. W., 199, 220 Woolsey, C. N., 27, 28, 33, 47, 49, 50, 58, 63, 74, 89,1.37 Woringcr, E., 77, 137 Wouters, M., 221, 222, 224: 262 Wright, S., 269, 312 \\'yers, E., 163, 196

Y Yakovlev, P. I., 14, 17, 20, 27, 28, 30, 32, 34 Yokota, T., 80, 90, 91, 138 Young, M. W., 88, 138 Yoiiniss, J., 163, 193

Z Zabarenko, L. \I., 14.1, 195, 196 Zalnrailson, A. N., 175, 196 %nltsln:lIl, l'.. 203, 204, 208. 21') Zanchetti, A,, 53, 54, 74 Zeller, E. A,, 203, 208, 2118 Ziegler, hl. H., 203, 216 Zieve, L., 148, 196 Zimdahl, \I7. T., 202, 220 Ziminerinnn, I;. T., 144, 143. 196 Zironcloli, A,. 110, 137 Zottcrmaii, Y.,36, 38, 75 Zubck, J. P., 144, 145, 103 Zuckcrkandl, E., 7, 9,20, 34 Zunino, C., 23, 34

SUBJECT INDEX A

B littrbiturates, effect on, Iiippocanipus, 105-107 Icarning, 146-148

l-B~nzyl-2,5-climc.tliylstwtonin Bc.iiwtyzine, effect on EEG, 291 U(~iperido1,structure of, 254 1-1~~~1r~yl-2,5-di1netliylserotonin, efIect on hippocampus, 9 3 13c\tainr, effect on schizophrenia, 211 Br'iin \vaves, popiilation characteristics and, 269270 ( Sce also Electroencey7halograms) 13rdotcnin, cflcct on KEG, 291 Iialliicinogenic properties of, 710 in schizophrenia, 204 Uiityrdictone, effect on EEG, 296 Biitprophenoncs, aromatic substitutions of, 225 with morphine-like potency, 221263 H i i t y q Iprrazine, structure of, 253

]>AS,

Acetophenazine, structure of, 253 Acetylcholine, effect on hippocanilms, 94-9,5, 98, 120 Ahnomycin D, eiiect on learning, Atlrenaline, in schizophrenia, 205 .klrcncrgic agents, elFects on EEG's, 300-303 effects on hippocampus, 99-100 Alcoholism, tryptophan metabolism in, 214 Aluminum hydroxide, topical application t o cercbral cortex, 163 Amine ( s 1, hiogenic, i r i mental illness, 197-220 nietal>olism, in schimphrenia, 20221% y-Aminobutyric acid-glrrtamic acid system, nc~iroleptii~drug cllccts and, 256-260 Amplrt~taininr, eff'rsct mi KEG, 284-285, 308 cxffect on it..iriiing, 148-149 Iicmc&ial, 171-172 nirth-, cl1ei.t on learning, 173 Ancisthtxtics, effect on hippocaml)iis, 104-110 Anisospirol, structure of, 253 Anticholinergic drugs, effect on, hippocampus, 102-104 learning, 159-1 60 Arccolinc, effect on Icarning, 173 Atropine, effrct on EEG, 286-257, 293 effect on hippocampus, 102-1o:j cffect on learning, 159-160, 173 methyl-, effect on lcwning, 160 K-Azagumine, effect on leurning, 165166

C Cafkeine, beiieficial effect on mcmory, 186 c4fcct on EEG, 288, 308 Gilciinn, eifect on learning, 174-175 Carh:ichol, effect on hippocampus, 120 C ~ i t ~ i I ~ ~ ~ i s y - ~ ) r odrugs, duciii~ 228-229, 247 (:;t~ccholamines, c+€cct on EEC, 283, 300-302 in mental illness, 197-220 iirinary, in stress, 216 ( Sve also individual compounds) (htioiis, effect on learning, 174-175 (:(mtriil nervous system, clrugs infliiciicing learning and, 188-189