Advances in the Study of Behavior, Volume 6

Advances in THE STUDY OF BEHAVIOR VOLUME 6 Contributors to This Volume P. P. G. BATESON BENNETT G. GALEF, JR. SARAH ...

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Advances in

THE STUDY OF BEHAVIOR VOLUME 6

Contributors to This Volume P. P. G. BATESON BENNETT G. GALEF, JR. SARAH BLAFFER HRDY J. B. HUTCHISON PAUL ROZIN GEORGE N. WADE

Advances in

THE STUDY OF BEHAVIOR Edited by JAY S. ROSENBLATT Institute of Animal Behavior Rutgers University Newark, New Jersey

ROBERT A. HINDE Medical Research Council Unit on the Development and Integration of Behavior University Su b-Department of Animal Behavior Madingley, Chmbridge, England

EVELYN SHAW Department of Biological Sciences Stanford University Stanford, California

COLINBEER Institute of Animal Behavior Rutgers University Newark, New Jersey

VOLUME 6

ACADEMIC PRESS

New York San Francisco London 1976 A Subsidiary of Harcourt Brace Jovanovich, Publishers

COPYRIGHT 0 1976, BY ACADEMIC PRESS,INC. ALL RIGHTS RESERVED. NO PART O F THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER.

ACADEMIC PRESS, INC.

11 1 Fifth Avenue, New York, New York 10003

Wniled Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road. London N W l

LIBRARY OF CONGRESS CATALOG CARD NUMBER: 64-8031 ISBN 0- 12-004506-0 PRINTED IN THE UNITED STATES O F AMERICA

Contents

..................................... Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contents of Previous Volumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . List of Contributors.

ix

xi xiii

Specificity and the Origins of Behavior P. P. G . BATESON

.................................. .........

1 2

Determinants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. The Nature of “Relevant” Experience, . . . . . . . . . . . . . . . . . . . V. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8 12 17 18

I. Introduction..

11. Initial Determinants in the Development of Behavior 111. Classification of Behavior in Terms of Developmental

The Selection of Foods by Rats, Humans, and Other Animals PAUL ROZIN

I. Solutions to the Food Selection Problem . . . . . . . . . . . . . . . . . 11. Rats: An Example of Successful Generalists . . . . . . . . . . . . . . . 111. Food Selection in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21 27 52 67

Social Transmission of Acquired Behavior: A Discussion of Tradition and Social Learning in Vertebrates BENNETT G. GALEF, JR.

I. Introduction.,

.................................. V

77

vi

CONTENTS

I1. I11. I v. V.

Field and Associated Laboratory Studies . . . . . . . . . . . . . . . . . Learning and Conditioning Paradigms . . . . . . . . . . . . . . . . . . . Problems of Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81 88 92 95 97

Care and Exploitation of Nonhuman Primate Infants by Conspecifics Other than the Mother SARAH BLAFFER HRDY I. I1. I11. IV V. VI

. .

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Male Care vs . Exploitation of Infants . . . . . . . . . . . . . . . . . . . . Nurture vs . Abuse-Male and Female Roles . . . . . . . . . . . . . . . . The Pros and Cons of Aunting . . . . . . . . . . . . . . . . . . . . . . . . Selective Pressures on the Infant ....................... Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

101 104 118 120 142 148 150

Hypothalamic Mechanisms of Sexual Behavior. with Special Reference to Birds J . B. HUTCHISON Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Localized Steroid Effects in the Brain .................... Biochemical Factors in Androgen Action . . . . . . . . . . . . . . . . . Variable Hypothalamic Sensitivity to Androgen . . . . . . . . . . . . . Hypothalamic Androgen Concentration and the Structure of Courtship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI . Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I. I1. I11. IV . V.

159 160 165 173 185 190 194

Sex Hormones. Regulatory Behaviors. and Body Weight GEORGE N .WADE I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Influence of Sex and Reproductive Condition . . . . . . . . . . . . . . 111. Activating Effects of Sex Hormones: Gonadectomy and Replacement Therapy in Adults ....................... IV . Site and Mechanism of Action of Estradiol and Progesterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

201 203

207 215

CONTENTS

V . Development of Responsiveness to Ovarian Steroids and Effects of Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI . Sex Differences in Neuroendocrine Regulation of Body Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII . Hormonal Effects on Taste Preferences and Dietary Self-Selection ................................... VIII . Hormones and Weight Regulation in Nonrat Species . . . . . . . . . . IX . Conclusions and Directions for Future Research . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Subject Index

.........................................

vii

237 243 253 260 264 267

281

This Page Intentionally Left Blank

List of Contributors Numbers in parentheses indicate the pages on which the authors' contributions begin.

P. P.G. BATESON, Sub-Department of Animal Behaviour, University of Cambridge, Cambridge, England ( 1 ) BENNETT G. GALEF, Jr., Department of Psychology, McMaster University, Hamilton, Ontario, Canada ( 7 7 ) SARAH BLAFFER HRDY, Peabody Museum, Harvard University, Cambridge, Massachusetts ( 1 01) J.B. HUTCHISON, MRC Unit on the Development and Integration of Behaviour, University Su b-Department, Madingley, Cam bridge, England ( 159) PAUL ROZIN, Department of Psychology, University of Pennsylvania, Philadelphia, Pennsylvania (21) GEORGE N. WADE,Department of Psychology, University of Massachusetts, Amherst, Massachusetts (201)

ix


Preface The study of animal behavior is attracting the attention of ever-increasing numbers of zoologists and comparative psychologists in all parts of the world, and is becoming increasingly important to students of human behavior in the psychiatric, psychological, and allied professions. Widening circles of workers, from a variety of backgrounds, carry out descriptive and experimental studies of behavior under natural conditions, laboratory studies of the organization of behavior, analyses of neural and hormonal mechanisms of behavior, and studies of the development, genetics, and evolution of behavior, using both animal and human subjects. The aim of Advances in the Study of Behavior is to provide workers on all aspects of behavior an opportunity to present an account of recent progress in their particular fields for the benefit of other students of behavior. It is our intention to encourage a variety of critical reviews, including intensive factual reviews of recent work, reformulations of persistent problems, and historical and theoretical essays, all oriented toward the facilitation of current and future progress. Advances in the Study of Behavior is offered as a contribution to the development of cooperation and communication among scientists in our field.

xi


Contents of Previous Volumes

Volume 1 Aspects of Stimulation and Organization in ApproachlWithdrawal Processes Underlying Vertebrate Behavioral Development T. C. SCHNEIRLA Problems of Behavioral Studies in the Newborn Infant H. F. R. PRECHTL The Study of Visual Depth and Distance Perception in Animals RICHARD D. WALK Physiological and Psychological Aspects of Selective Perception GABRIEL HORN Current Problems in Bird Orientation KLAUS SCHMIDT-KOENIG Habitat Selection in Birds P. H. KLOPFER and J. P. HAILMAN Author Index-Subject Index

Volume 2 Psychobiology of Sexual Behavior in the Guinea Pig WILLIAM c. YOUNG Breeding Behavior of the Blowfly V. G. DETHIER Sequences of Behavior R. A. HINDE and J. G. STEVENSON The Neurobehavioral Analysis of Limbic Forebrain Mechanisms: Revision and Progress Report KARL H. PRIBRAM

xiii

XiV

CONTENTS OF PREVIOUS VOLUMES

Age-Mate or Peer Affectional System HARRY F. HARLOW Author Index-Subject Index

Volume 3 Behavioral Aspects of Homeostasis D. J. McFARLAND Individual Recognition of Voice in the Social Behavior of Birds C. G. BEER Ontogenetic and Phylogenetic Functidns of the Parent-Offspring Relationship in Mammals LAWRENCE V. HARPER The Relationships between Mammalian Young and Conspecifics Other Than Mothers and Peers: A Review Y. SPENCER-BOOTH Tool-Using in Primates and Other Vertebrates JANE van LAWICK-GOODALL Author Index-Subject Index

Volume 4 Constraints on Learning SARA J. SHETTLEWORTH

.

Female Reproduction Cycles and Social Behavior in Primates T. E. ROWELL The Onset of Maternal Behavior in Rats, Hamsters, and Mice: A Selective Review ELIANE NOIROT Sexual and Other Long-Term Aspects of Imprinting in Birds and Other Species KLAUS IMMELMA" Recognition Processes and Behavior, with Special Reference to Effects of Testosterone on Persistence R. J. ANDREW Author Index-Subject Index

CONTENTS OF PREVIOUS VOLUMES

Volume 5 Some Neuronal Mechanisms of Simple Behavior KENNETH D. ROEDER The Orientational and Navigational Basis of Homing in Birds WILLIAM T. KEETON The Ontogeny of Behavior in the Chick Embryo RONALD W. OPPENHEIM Processes Governing Behavioral States of Readiness WALTER HEILIGENBERG Time-sharing as a Behavioral Phenomenon D. J. McFARLAND Male-Female Interactions and the Organization of Mammalian Mating Patterns CAROL DIAKOW Author Index-Subject Index

xv


Specificity and the Origins of Behavior P.P.G.BATESON SUB-DEPARTMENT OF ANIMAL BEHAVIOUR UNIVERSITY OF CAMBRIDGE CAMBRIDGE, ENGLAND

I.

Introduction

....................................

............ 111. Classification of Behavior in Terms of Developmental Determinants . . . . Iv. The Nature of “Relevant” Experience ..................... V. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Initial Determinants in the Development of Behavior.

I.

1

2 8 12 17 18

INTRODUCTION

What factors during development determine the special ways in which an individual animal eventually will behave? What decides the specific form and patterning of its behavior? What gives a behavior pattern its unique character, making it different from other behavior patterns? It would be useless to pretend that the attempts to answer these questions about the ontogeny of behavior bring widespread agreement. Nor is there harmonious consensus among those who study behavior as to the ways these questions should be answered or even about the nature of relevant evidence. The debate about the best ways to study behavioral development has, of course, been extensive (see Barnett, 1973; Beach, 1955; Dawkins, 1968; EiblEibesfeldt, 1961, 1970; Ewer, 1971; Hailman, 1967; Hebb, 1953; Hinde, 1968, 1970a; Jensen, 1961; Konishi, 1966; Kuo, 1967; Lehrman, 1953, 1970; Lehrman and Rosenblatt, 1971; Lorenz, 1961, 1965; Moltz, 1965; Schneirla, 1956, 1966; Thorpe, 1956, 1963; Tinbergen, 1963). It would be quite wrong to suggest that nothing has been achieved as a result of this debate. In particular, many of the disagreements have been shown to arise from differences in interest and emphasis. Those ethologists influenced by Lorenz have been primarily interested in the origins of behavioral adaptiveness, whereas others studying behavior, par-

2

P.P. G . BATESON

ticularly those who were influenced by the writings of Kuo, Schneirla, and Lehrman, have been principally concerned with development in the individual animal. Even though this point was clarified many years ago (eg., Tinbergen, 1963), the controversy has rumbled on. Despite frequent announcements of the death of the natureimrture dichotomy of behavior, a distinction between activities that are learned and those that are not is still widely used. In part this has been because classifications of the origins of behavior have been frequently muddled with classifications of behavior itself. To state that inheritance and the environment determine the characteristics of behavior is not the same as urging that all behavior patterns can be divided into those that are inborn and those that are environmentally determined. As I shall point out later, a residual confusion between the sources of behavioral distinctiveness and the origins of its adaptiveness is still found in the literature. I believe, however, that the reasons for the persisting, wide and often bitter differences of viewpoint are much more deeply seated than could be explained by mere errors of logic. In this chapter the possibility is explored that different people perceive the same body of data in different ways. Where some see sharp discontinuities, others see smooth gradations, and, accordingly, classifications differ. In order to develop the argument, I shall first consider factors in development that are responsible for the distinctiveness of behavior. 1 believe that when these sources of difference are scrutinized, it becomes much easier to understand why classifications of behavior in terms of developmental origins have generated so much heated argument.

11. INITIAL DETERMINANTS IN THE DEVELOPMENT OF BEHAVIOR It is customary now to distinguish between the factors that control behavior from moment to moment and those that are responsible for its development (e.g., Hinde, 1970a). The distinction may not always be easily drawn in practice since a factor responsible for the development of a behavior pattern may lie close in time to the occurrence of that behavior. In general, though, sources of behavioral distinctiveness usually lie considerably farther back in time from the behavior they affect than controlling conditions. Developmental determinants are initiating agents that lastingly give a behavior pattern its peculiar characteristics differentiating it from other types of behavior; of course, a lasting effect is not necessarily irreversible under all conditions. Once one starts to trace back through the nexus of events that precede a behavior pattern, there might seem no obvious stopping point. However, what is usually meant by a developmental determinant of an individual’s behavior is a factor that was responsible for the distinctiveness of the individual’s behavior

SPECIFICITY AND THE ORIGINS OF BEHAVIOR

3

TABLE I A CLASSIFICATION OF DEVELOPMENTAL DETERMINANTS OF BEHAVIOR Determinants with specific effects

Determinants with general effects

Inherited

A

B

Environmental

C

D

Determinants

and which operated at some point in the life of that individual. Wherever I refer to “determinant” in this chapter I use it in this special sense. Few people would disagree nowadays that part of the initial determinants of behavior are already present in latent form within the fertilized egg; some determinants are, perhaps, present as cytoplasmic factors, but most are represented in the nucleus of the zygote-presumably in genetically coded form. An important semantic issue is at what stage a gene is to be treated as a developmental determinant. I believe a gene would generally be regarded as a determinant at the time of its activation. However, t o discover the actual moment when gene expression occurs for the first time is an extraordinarily difficult task for embryology, and most statements about inherited determinants will be based on inference rather than evidence. There is also widespread acceptance that other necessary conditions for the development of any pattern of behavior lie in the environment in which the animal grows up. Difficulties and disagreements arise, however, because both the inherited and the environmental determinants of behavior can be further subdivided into those that exert specific effects and those that have general effects. 1. General and Specific Effects of Determinants

It is important to ask whether it is possible to draw a sharp line across the continuum that runs from those determinants affecting only one pattern of behavior to those having such general effects they are necessary for life itself. In principle, though, the determinants of behavior could be placed somewhere in the matrix shown in Table I. An example of A might be the gene affecting the hygienic behavior in honeybees (Apis mellvera) that involves the uncapping of hive cells containing diseased larvae (Rothenbuhler, 1967). A representative of B might be a gene that affects the responsiveness of Drosophilu melanogaster to light (Benzer, 1967); loss of responsiveness to light, not surprisingly, has a widespread effect on all visually guided activities. An example of C might be the experience of chicks (Callus gullus) that have pecked at small objects painted with bitter-tasting substances; as a result, they develop a selective aversion for pecking at these objects (e.g., Lee-Teng and Sherman, 1966). Finally D might be

4

P. P. G.BATESON

early experience of crowded conditions by locusts (Locusra migratoria) subsequently leading them to become migratory (Ellis, 1964). The distinction between specific and general effects of determining events poses a number of difficulties. How can we ever be certain that a determining event has only one outcome? Any determinant that seems to have a highly specific effect on behavior is in danger of being reclassified as having more general consequences after further study. For example, further analysis of the honeybee may show that the genes affecting hygienic behavior have pleiotropic effects on other dissimilar behavior patterns. Even after the most convincing demonstration that differences between one animal and another in the way they make nests, say, is dependent on differences in the way they were reared, an experimenter is in no position to claim that other differences in behavior will not subsequently be found. On the other hand, if he finds that the experimental operation is the source of differences in nest-building, aggressive behavior, and feeding, he would probably not even wish to claim that it had highly specific effects. Therefore, it might seem that the categories of determinants with specific outcomes are liable to be eroded by the collection of fresh evidence, and individual cases will tend to move t o the right in the matrix shown in Table I. However, if a determinant affects a number of apparently different types of behavior, does it necessarily mean that its consequences are general? Could not those categories be thought of as having some special feature in common? Perhaps the determinant imposes some constraint on the way the animal’s head can be moved and this limitation shows up most noticeably when the animal is making a nest, threatening another individual, or feeding. Alternatively the nonspecific effects on behavior may themselves turn out to be consequences of a highly specific behavioral outcome of a developmental process. The point is, then, that the placing of a particular determinant in the matrix shown in Table I is always subject to alteration in either direction as fresh evidence becomes available. A related point is that a decision on how to classify a determinant may depend critically on the level at which its consequences are assessed. For example, phenylketonuria is a hereditary disease which, among other things, results in rather general disorders of behavior. However, the disease is caused by a specific deficiency of the liver enzyme phenylalanine hydroxylase (Hsia, 1967). Does the classifier utilize this knowledge about the specificity of the genetic determinants of the disease at the biochemical level? Or does he, as seems more logical, consistently apply behavioral criteria throughout and classify the determinants of phenylketonuria as having general effects?

2.

The Problem of Behavioral Units Another issue impinges crucially on the distinction between specific and general consequences. How should behavior patterns themselves be divided up? Are


5

there obvious units that would provide a basis for the distinction between one behavior pattern being affected by some preceding event and many patterns being affected? It is an important question, but, once again, there is little agreement about the answer to it. The traditional response of many ethologists has been to argue that “natural” units of behavior become apparent to anyone who knows and loves his animals. On this view it is possible to assemble an ethogram-a complete inventory of behavior patterns shown by a species. However, thoughtful reviewers of the field have pointed out that selection of evidence is inevitable in the study of animal behavior as in everything else and that any ethogram will reflect the interests and preconceptions of its compiler (see, e.g., ‘ Marler and Hamilton, 1966, pp. 71 1-717; Hinde, 1970a, pp. 10-13). Furthermore, many difficulties remain even when it is possible to obtain agreement about the ostensive definition of a behavior pattern after pointing it out as it occurs or after detailed description. For instance, the same display given in two different contexts may serve two different biological roles in communicaton; although the message is the same the meaning is different in each case (e.g., Smith, 1968). For purposes of classification, do we have two behavior patterns or one? Another illustration is provided by the great tit (Pants major) which hammers with its bill in exactly the same way when it is feeding and when faced with a stimulus that evokes attack. Blurton-Jones (1968) argued that the behavior patterns are different because h a found that one increased in frequency after food-deprivation but the other did not. His experiment did not settle the matter, as Andrew (1972) points out, because the motor pattern of hammering may be controlled by the same stimulus in both cases. The food-deprived great tit may hammer more frequently at food because, as a result of its own searching behavior, it sees more food than objects evoking attack. So we are left with the dilemma whether or not we should split or lump bill-hammering in the two situations. Yet another difficulty is that, even with the most unequivocal items of behavior for inclusion in a classic ethogram, the temporal pattern of occurrences may be such that different measures of the behavior yield different results. For instance, the “chink” call given by chaffinches (Fringillla coelebs) when mobbing potential predators first increases in frequency and then declines gradually. Now, when Hinde (1960) measured the response of chaffinches to a stuffed owl and a toy dog, he found that on three measures the owl was more effective than the dog; the chaffinches called more at the owl than at the dog during the first 6 minutes of presentation; they responded more rapidly to the owl; and their calling at the owl waned more slowly. However, the time taken t o reach the peak rate of calling was shorter when the birds were presented with the dog; the birds’ calling in response to the dog apparently warmed up more quickly than was the case with the owl. In order to account for results such as these, it is necessary to postulate a number of underlying processes that interact to produce the temporal pattern of calling (Hinde, 1970b). Where does that leave the treatment of “chinking” as a unitary end product of development?

6

P. P. G.BATESON

Whatever way one chooses to deal with this particular example, it serves to warn that the types of measure chosen may have a profound effect on the interpretation of how the behavior is controlled and initially determined. It is easy to lose patience with arguments such as these on the grounds that, despite some imprecision, most people know what they are talking about. But how public are the rules that each of us uses? The difficulties in communication are not trivial and, indeed, present a major problem to philosophers. The issue is stated succinctly by Goldman (1970, p. 1) at the beginning of a book devoted t o the topic. He writes: Suppose that John does each of the following things (all at the same time): ( I ) he moves his hand, (2) he frightens away a fly, (3) he moves his queen to king-knightseven, (4) he check mates his opponent, (5)he gives his opponent a heart attack, and ( 6 ) he wins his first chess game ever. Has John here performed six acts? Or has he only performed one act, of which six different descriptions have been given?

The relevance of this problem to my argument is that the way in which behavior is divided up into units is very much a matter of opinion which, in turn, is 3 reflection of what questions about behavior are considered t o be important. The relative weights given by the classifiers to factors involved in development and control, to context, to consequences of behavior, and to its biological function differ from one school of thought t o the next. Classifications of behavior depend very much on the interests of the compiler and what may seem a natural unit from one vantage point may not even be noticed from another (cf. Hinde, 1970a). A decision about how finely behavior should be divided or about what features of behavior are important would obviously have profound effects on the placing of determinants on the specific-general scale. For example, if a gene affects all aspects of migratory behavior in a bird, its effects would be treated as specific if migration is regarded as a single pattern of behavior and nonspecific if the different aspects of migration were regarded as separate activities.

3. A Continuum in Effects of Determinants A final difficulty that threatens a simple division of determinants into those with specific outcomes and those with general ones is the likelihood of continuity. If one category of conditions affects single patterns of behavior and another category of conditions affects all the behavior patterns in an animal’s repertoire, every type of intermediate between these two extremes is possible in principle. In practice, intermediates are posing difficulties for simple dichotomies. For instance, an important criterion used to characterize conditions responsible for learning is that the lasting consequences on behavior of these training conditions are limited in extent. If environmental conditions have diverse effects on behavior persisting for a long time, those effects are not ordinarily attributed to learning. For example, when a rat is handled early in infancy and subsequently its behavior is found to be affected in a whole variety of


7

different ways, it is not thought to have learned anything as a result of the handling. Nevertheless, the line of demarcation is arbitrary. Again, when kittens are exposed to vertical or horizontal lines at a particular stage in development, the kittens are subsequently said to be unresponsive to lines placed at right angles to the familiar orientation (Blakemore and Cooper, 1970; Blakemore, 1973). In some ways these effects are rather similar to those of imprinting in which a bird's social responsiveness is narrowed down'to the familiar object. However, the birds have no difficulty in detecting unfamiliar conspicuous objects which they actively avoid, whereas the kittens appear to be unable to detect lines of unfamiliar orientation. Consequently, all behavior patterns dependent on the detection of lines placed at right angles to the familiar orientation would presumably no longer occur in the kittens, and the effect of their early experience would have much more general consequences than that of the young birds. Most people would now want to treat imprinting as an example of learning, but the effects of restricted visual experience on the kittens is much less easily classified. It is worth noting that even the effects of imprinting are relatively nonspecific in as much as the learning process affects the subsequent occurrence of nonsocial behavior such as feeding and grooming by narrowing the range of objects with which the bird associates. In the absence of the mother or her substitute, the birds will generally abandon all other activities while they search for her. Furthermore, imprinting has marked facilitating and constraining effects on what the animal can subsequently learn (Bateson, 1973). Both Schneirla and Lehrman were concerned about the arbitrary way in which ethologists and experimental psychologists alike have so neatly demarcated the conditions necessary for learning from other types of experience. Lehrman (1970, p. 32) illustrated the conceptual problem facing us by sketching in the stages between environmental conditions having very general effects and those having highly specific effects. He listed the following points on the continuum : 1 . Effects on neural development of nonbiological conditions (temperature, light, chemical conditions in the environment). 2. Nonspecific effects of gross stimulus input. 3. Developmental effects of practice passively forced during ontogeny. 4. Developmental effects of practice resulting from spontaneous activity of the nervous system. 5. Links and integrations between behavioral elements resulting from early, nonfunctional partial performances. 6. Interoceptive conditioning resulting from inevitable tissue changes and metabolic activities. 7. Simple conditioning to stimulation resulting from spontaneous movements. 8. Simple instances of conventional conditioning and learning.

8

P. P. G . BATESON

Where does all this take us, then? A classification of determinants into those that have specific effects and those that have general effects is likely to be revised as fresh evidence is collected. Furthermore, it assumes a classification of behavioral units or types about which there may not be widespread agreement. Finally, it cuts arbitrarily across a continuum. None of these points render such a classification useless but they do mean that a sharp distinction between determinants with specific and general effects may create conceptual difficulties when attempts are made to unravel the processes involved in development. 111. CLASSIFICATION OF BEHAVIOR IN TERMS OF

DEVELOPMENTALDETERMINANTS So far I have tried to outline the difficulties inherent in one classification that rests in part on the nature of longlasting effects on behavior. It is now useful to reverse the procedure and consider a classification of behavior patterns in terms of developmental determinants. Naively it might be supposed that correspondence can be found between the two classifications. Indeed, preformationist views have from time to time slipped into ethological discussions of the origins of behavior. Behavior patterns are sometimes thought of as encapsulated in latent form in the fertilized egg; they are like Japanese flowers that will unfurl under the right environmental conditions. But even the most ardent preformationist does not insist that the blueprint for behavior, to use Lorenz’s metaphor, is the same as bricks, mortar, and a work force. In other words, even for the extreme nativist, a host of environmental conditions will obviously be necessary if the behavior pattern is to develop. Therefore it is not necessary to consider a class of behavior patterns that might be determined by a single factor alone. A much more plausible class is one in which the determinants of the behavior patterns are of the type shown in Fig. 1. In this case, a behavior pattern can be determined by one or more factors specifically affecting it as well as by one or more determinants that have general effects. In the example given in Fig. 1, each letter could represent many determinants each of which had the long-term inDETERMINANT A

h

t

2 3I0

a

d2-

A A

gz

0

W

z

I -

z

3 E

0

1 1

, ,

2

4

1 1 6

~ ~ 8 TWO-DAY

1 1 10

~ ~

MEANS

1 1 I2

~ ~ 14

1 1 16

~ ~

iof 1011 10 day1

~ ~

FIG. 4. Effect of estradiol benzoate (EB) and testosterone propionate (TP), alone or in combination with the antiestrogen, MER-25,o n running wheel activity in castrated male rats. (From Roy and Wade, 1975a.l

~ ~

" "

210

GEORGE N. WADE

It was noted above that eating and body weight are stimulated more by low doses of testosterone propionate than by high doses. Thomas Gentry has replicated and extended these findings. A low dose of testosterone propionate (200 pglday) stimulated both eating and weight gain in castrated male rats, whereas higher doses (1 or 2 mg/day) had no effect on eating and actually reduced weight gain (particularly during prolonged treatments-2-6 weeks). These data suggest that with the higher doses of testosterone propionate significant amounts of the androgen are being aromatized, and i t is the estrogens that may be causing the weight loss. To test this possibility, Gentry treated castrated male rats with four doses (200 pg, 1 mg, 2 mg, or 20mglday) of the nonaromatizable androgen, dihydrotestosterone propionate, and measured eating and weight gain. None of the four doses of dihydrotestosterone propionate was as effective as 200 pg of testosterone propionate in stimulating eating and weight gain in castrated males, but none decreased body weight. Finally, Gentry found that the weight-reducing actions of high doses (1 mg/day) of testosterone propionate were prevented by concurrent injections of progesterone (5 mg/day). Castrated males treated with lmg testosterone propionate -!- 5 mg progesterone gained nearly as much weight as those treated with 200 pg testosterone propionate alone. In female rats progesterone effectively attenuates the weightdepressing effects of estradiol benzoate (Section 111,B). Of course, progesterone alone has n o effect on body weight in castrated male rats. Unlike testosterone, the four doses of dihydrotestosterone propionate were equally effective in stimulating eating and weight gain. These data are certainly consistent with our hypothesis that with very high doses of testosterone significant amounts of aromatization occur and counteract the anabolic actions of testosterone. They also indicate that testosterone does not have to be reduced to dihydrotestosterone t o stimulate weight gain (Gentry and Wade, 1975). B.

FEMALES

The effects of gonadal hormones on behavioral regulation of body weight are more striking and somewhat more complicated in female rats than in males. Ovariectomy of adult female rats increases food intake and nest-building, decreases voluntary exercise, and markedly accelerates weight gain (Fig. 2) (Kakolewski etal., 1968; Rosenblatt, 1967; Stotsenburg, 1913; Wang, 1923). Note that these behavioral changes are qualitatively and quantitatively similar to those occurring during pregnancy, pseudopregnancy, lactation, and preceding puberty (see Table I). These data suggest that so far as weight-regulating behaviors are concerned noncycling females are functionally ovariectomized (Wade, 1972). Withdrawal of ovarian estradiol is probably responsible for the behavioral changes following spaying. Daily treatment with physiological doses of estradiol

HORMONES AND BODY WEIGHT

21 1

benzoate is sufficient to restore preovariectomy levels of eating, voluntary exercise, and body weight (Stern and Murphy, 1972; Tarttelin and Gorski, 1973; Wade, 1975; Zucker, 1969, 1972). Estradiol increases activity and decreases eating and body weight (see Table I). Although the constant daily doses of estradiol benzoate stimulate activity and inhibit appetite, there is no noncircadian cyclic fluctuation in these behaviors, suggesting that the cyclicity observed in intact females is due to rhythmic changes in steroid secretion, rather than to some endogenous cyclicity in responsiveness to steroids (Gerall e t al., 1973). Attempts to induce cyclic behavior with exogenous steroids have met with mixed success (Kennedy, 1964; Tarttelin and Gorski, 1973). Treatment of ovariectomized rats with a wide range of doses of progesterone (0.5-10 mdday) has no effect on eating, activity, o r body weight, but it does depress activity and stimulate eating and weight gain when given to intact female rats (Galletti and Hopper, 1964; Hervey and Hervey, 1966; Roberts et al., 1972; Rodier, 1971; Ross and Zucker, 1974; Wade, 1975;Zucker, 1969). In addition, progesterone given to ovariectomized, estradiol-treated rats can attenuate or completely block the actions of estradiol on behavior and body weight in a dose-dependent fashion (Roberts etal., 1972; Rodier, 1971; Ross and Zucker, 1974; Wade, 1975; Zucker, 1969). Thus, the following data have led us (Wade, 1972; Wade and Zucker, 1969a; Zucker, 1972) to hypothesize that estradiol is the principal ovarian steroid affecting behavioral regulation of body weight in rats and that the principal role of progesterone is simply to attenuate the actions of estradiol: ( I ) estradiol benzoate alone reverses the ovariectomy-induced changes in eating, activity, and body weight, whereas progesterone has no effect on any of these measures in ovariectomized rats; (2) progesterone inhibits activity and stimulates eating and weight gain in intact or spayed, estrogen-treated rats; (3)progesterone and ovariectomy cause quantitatively and qualitatively similar changes in behavior and in body weight and composition (Galletti and Hopper, 1964; Hervey and Hervey, 1966; Rodier, 1971 ;Wade, unpublished data); (4) the effects of progesterone and ovariectomy are not additive, suggesting a common mode of action (Galletti and Hopper, 1964; Hervey and Hervey, 1966). These data suggest that high plasma progesterone titers functionally ovariectomize female rats by inhibiting the actions of estradiol in the brain and perhaps by inhibiting estradiol secretion in intact females. These two possible modes of action are not mutually exclusive, of course. Antiestrogenic actions of progesterone on peripheral tissues and estrous behavior are welldocumented in rats (e.g., Courrier, 1951; Powers and Zucker, 1969; Rothchild, 1965). It has been suggested that high plasma progesterone titers may competitively inhibit uptake of tritiated estradiol by rat brain tissues (Anderson and Greenwald, 1969; Lisk, 1974), although this effect is at least somewhat difficult t o demonstrate (Wade, unpublished data) and awaits further clarification.

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The fluctuations in regulatory behaviors, body weight, and ovarian steroid secretion during estrous cycles, pregnancy, and pseudopregnancy are consistent with our hypothesis that levels of food intake and voluntary exercise are determined by plasma estradiol-to-progesterone ratios (estradiol availability). Blood estradiol levels peak on the morning of proestrus (Hori et al., 1968; Yoshinaga etal., 1969), just before activity peaks and eating drops. Ter Haar (1972) has shown a close correspondence between blood estradiol levels and hour-to-hour changes in food consumption during the estrous cycle. At diestrus, estradiol-toprogesterone ratios are much lower (Hori et al., 1968; Hashimoto et al., 1968; Uchida el al., 1969), activity declines, and eating and body weight rise. This, of course, raises a question as to the role of the preovulatory progesterone peak (Feder et al., 1968) in the control of these regulatory behaviors. Stem and Zwick (1972) have shown that ovariectomy of cycling females just after the proestrous estradiol peak, but prior t o the preovulatory progesterone surge, does not alter their activity peak. These data suggest that estradiol, but not progesterone, is essential for the surge in running. This dissociates hormonal control of running wheel activity and estrous behavior, since preovulatory progesterone is essential for the occurrence of sexual receptivity (Powers, 1970). Similar experiments have not been performed with eating behavior. It is possible that the progesterone peak contributes to the decrease in running and the increase in eating on the day following proestrus. During pregnancy and pseudopregnancy, ovarian estradiol secretion is very low, plasma progesterone titers are elevated (Hashimoto et al., 1968; Yoshinaga etal., 1969), and levels of eating and exercise are very similar to those after ovariectomy (Table I). We have suggested previously that these extremely low estradiol-to-progesterone ratios may cause a functional ovariectomy so far as food intake and locomotor activity are concerned (Wade and Zucker, 1969a): the high progesterone levels may be sufficient to block completely the actions of the small amounts of circulating estradiol. Although estradiol and progesterone have rather striking effects on regulatory behaviors and body weight in rats and these measures are highly correlated with estradiol availability, this does not necessarily mean that these are actually the active steroids in target tissues. Some of our uptake work with radioactive steroids suggests that both estradiol and progesterone are metabolized to other compounds in the brain. After injection of ovariectomized rats with tritiated estradiol, substantial quantities of estrone are found in the brain in addition to estradiol (Feder et al., 1974b), but little was known about the effects of estrone on energy balance in rats. Similarly, rat brain extensively metabolizes progesterone. Just 4 hours after subcutaneous injection of tritiated progesterone, only about 25% of the brain radioactivity remains as unmetabolized progesterone (Wade et al., 1973). Karavolas and Herf (1971) have demonstrated that rat hypothalamic tissue reduces progesterone to 5a-pregnane-3,20-dione and other Sa-

213


reduced metabolites in vitro. Again, nothing was known about the effects of these metabolites on eating and body weight. Recently, it has been shown that both estradiol and progesterone are more effective than their principal metabolites in affecting eating and body weight (Wade, 1975). Two micrograms of estradiol benzoate per day is more effective than 20 pg estrone benzoate in depressing food intake and body weight in ovariectomized rats (Fig. 5). Similarly, while 0.5 mg progesterone/day significantly increased eating and body weight in ovariectomized, estradiol-treated rats, 1 mg/day of 5a-pregnane-3P-ol-20-oneand Sa-pregnane3,20dione were completely without effect. Therefore, it is unlikely that either estradiol or progesterone must be converted to an active metabolite in the target tissues. Perhaps the significance of the estradiol and progesterone metabolism in the brain is simply that the metabolites are not active forms and have little effect on behavior (Wade, 1975). Our knowledge of the activational effects of sex steroids on thermoregulation is amazingly sparse considering the widespread use of basal body temperatures as a means of detecting ovulation in women. I am aware of no published studies on the effects of estradiol or progesterone administration on thermoregulatory behavior in rats, although it has been reported that nest-building increases after ovariectomy (Rosenblatt, 1967). In addition, we have recently found that gonadectomy causes a significant decrease in colonic temperatures of rats of both sexes (Fig. 1) (Marrone et ul., 1974). Work done primarily in human beings has led to the widely accepted hypothesis that progesterone is thermogenic (for reviews, see Kappas and Palmer, 1963; Rothchild, 1969). However, as Rothchild (1969) points out, labeling proges-

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SUCCESSIVE 3-DAY PERIODS

FIG. 5. Food intake (top) and body weight (bottom) of ovariectomized rats injected with estradiol benzoate (2 Wday), estrone benzoate, or sesame oil vehicle from day 7 through day 33. Estrone dose was increased from 2 to 20 &day as indicated by arrow. (From Wade, 1975.)

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terone “thermogenic” may be somewhat premature, since there is little evidence suggesting just how progesterone raises body temperature. It could just as well be acting to decrease heat loss rather than increasing heat production. In any event, the work on hormonal control of body temperature in women is less than definitive to say the least. One widely cited abstract suggests that progesterone raises and that “estrogen” lowers body temperature in ovariectomized rats, but n o mention is made of the magnitude of the temperature changes or of the steriod doses necessary to induce them (Nieburgs and Greenblatt, 1948). The temperature-raising effect of progesterone in ovariectomized rats has been confirmed (Freeman et al., 1970; Marrone et al., 1974). As little as 0.5 mg progesterone/day significantly raised body temperature in ovariectomized rats. One milligram or 5 mg progesterone/ day were roughly equivalent in raising rectal temperature (mean increase = 0.8OC) and were approximately twice as effective as 0.5 mg (mean increase = 0.4OC). The effects of all three doses were transient, and rectal termperatures returned to baseline within 2 weeks, in spite of continued progesterone treatment (Marrone etal., 1974). However, it is unlikely that progesterone alone accounts for the fluctuations in colonic temperature during the estrous cycle. Marrone has found that treatment of ovariectomized rats with three different doses of estradiol benzoate (1, 3, or 10 pg/day) also raises colonic temperature in a dose-dependent fashion (Marrone etal., 1974a). However, unlike progesterone, the lower dose of estradiol benzoate (1 pg) was substantially more effective in raising colonic temperature than were the higher doses. This finding contrasts with the earlier suggestions that estrogens lower body temperature in rabbits (Brown et al., 1970) and rats (Nieburgs and Greenblatt, 1948). However, these data indicating that low (and probably “physiological”) doses of both estradiol and progesterone raise colonic temperature in ovariectomized rats are certainly consistent with our finding that colonic temperature rises at proestrus (Section 11, A), just after blood estradiol and progesterone titers peak (Hashimoto et al., 1968; Yoshinaga et al., 1969). As mentioned previously, it is unlikely that the proestrous activity peak is totally responsible for the proestrous hyperthermia, although it may be a contributing factor. Progesterone, which has no effect on locomotor activity in ovariectomized rats (Rodier, 1971), significantly raises body temperature. In addition, high doses of estradiol benzoate (10 pg/day) are more effective than lower doses (1 pg/day) in stimulating running wheel activity in ovariectomized rats, but the lower dose was more effective in raising colonic temperature. It is clear that a great deal of additional research is needed before we can specify the hormonal factors affecting thermoregulation in rats. We have found it difficult even to replicate some of the older work in this field (Marrone et al.,


215

1974). Perhaps hormonal effects on body temperature require very narrowly defined environmental conditions to be evident, which may help to account for the irritating lack of progress in this area. Note that during the fluctuations in estradiol availability, energy intake and expenditure do not vary independently of one another. Rather, food intake consistently is inversely related t o activity and heat loss (see Table I). During times of high estradiol availability, energy expenditure exceeds intake, and this pattern is reversed during low estradiol availability. The consistent, although negatively related, coordination among energy balance-regulating behaviors has led several authors to suggest that similar or identical neuroendocrine mechanisms may control these several behaviors (Brobeck et ul., 1947; Kinder, 1927; Rothchild, 1967). In fact, in an extremely insightful review of a widely divergent literature, Rothchild (1967) has suggested that a single neurological change accounts for a wide variety of steroid-induced changes in reproductive physiology and behavior. Briefly, he has hypothesized that progesterone acts to inhibit the ventromedial hypothalamus, disinhibiting the lateral hypothalamus. The disinhibition of the lateral hypothalamus, in turn, causes an increase in appetite and prolactin secretion and inhibits heat loss, sexual receptivity, locomotor activity, and maximal-rate luteinizing hormone secretion. Although a number of data that do not seem consistent with this model have subsequently appeared, this was a remarkable attempt to integrate a wide variety of hormonerelated phenomena. Unfortunately, as is shown in the following, it is not possible to attribute all of these functions to a single neural system.

IV. SITE AND MECHANISM OF ACTION OF ESTRADIOL AND PROGESTERONE A.

SITE OF ACTION

In 1947, Brobeck et al. noted the rhythmic fluctuations in eating, exercise, and body temperature during estrous cycles and pseudopregnancy and suggested that one might consider the possibility that one or more of the hormones in question act upon the hypothalamic cells responsible for this regulation in such a way as to direct the overall energy exchange now towards the side of energy storage, now towards the side of energy expenditure. Whether this is indeed the case cannot be decided at the present time, but the problem appears to be one which lends itself to further experimental study.

The Brobeck et al. (1947) hypothesis that sex hormones act directly on hypothalamic neurons to alter regulation of energy balance seems to have been

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well ahead of its time, for, although their idea did, indeed, lend itself to further study, 16 years elapsed until additional data were published on this problem. In an exciting series of papers, Kennedy and Mitra (1963a,b,c; Kennedy, 1964) attempted to integrate much of the work suggesting that similar hypothalamic sites controlled gonadotropin release, eating behavior, estrous behavior, and voluntary exercise. Kennedy and Mitra reported that they could abolish some of the estrogenic effects on behavior with electrolytic lesions of specific hypothalamic loci. Ventromedial hypothalamic lesions seemed to abolish voluntary exercise ; neither estradiol benzoate, amphetamine, nor underfeeding stimulated exercise in lesioned rats. All of these treatments are effective in neurologically intact rats. Because he found n o treatment that increased exercise in rats with ventromedial hypothalamic lesions, Kennedy (1964) suggested that this brain region was not directly sensitive t o estradiol, but represented an integrative area where a variety of stimuli converged t o induce running. On the other hand, some lesions in the rostral hypothalamus selectively abolished estradiol-induced running. Animals with these lesions ran in response to amphetamine or underfeeding but not in response to exogenous estradiol benzoate. Kennedy (1964) concluded that the rostral hypothalamus contained estrogen-sensitive neurons that relay facilitatory s t i m d for activity to the ventromedial hypothalamus. He did not speculate as to where ovarian hormones might act t o affect eating or thermoregulation. Colvin and Sawyer (1969) provided tests of the Kennedy hypothesis by examining the effects of bilateral intracerebral implants of a 10% mixture of estradiol benzoate in cholesterol on locomotor activity in ovariectomized rats. They explored a wide variety of mid- and forebrain sites. As Kennedy predicted, positive sites where estradiol stimulated activity were located in the rostral basal diencephalon, whereas placements in the ventromedial hypothalamus were consistently negative. However, a variety of other positive sites was also found, including dorsal posterior hypothalamus and rostral midbrain. Colvin and Sawyer summarized by suggesting that their positive sites followed the course of the medial forebrain bundle. Latencies t o increase running in the responding animals averaged around 6 days. Intracranial implants of cholesterol alone were uniformly negative. At about the same time, Wade and Zucker ( 1 9 7 0 ~ )observed the effects of unilateral diencephalic implants of estradiol benzoate on both voluntary exercise and food intake in ovariectomized rats. We found that the estradiol benzoate implanted in the vicinity of the ventromedial hypothalamus significantly depressed food intake within 12 hours of application (Fig. 6). This effect was similar in magnitude to the changes in eating that follow systemic estradiol injection, and it lasted only as long as the estradiol was left in the brain (3 days)

217


open symbols

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FIG. 6.Coronal sections of the rat diencephalon indicating the location of hormone implants and their effectiveness in decreasing food intake. The response to progesterone (P) is indicated by the form of the symbol: circles, a decrease 10%; triangles, a 10-20% decrease, squares, a decrease 20%. Response to estradiol benzoate (EB) is indicated by degree of shading, regardless of the form of the symbol: a blank symbol indicates a decrease of 10%; a half-shaded symbol a decrease of 10-20%; and a black symbol a decrease of 20%. (From Wade and Zucker, 1970c.)

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20%. (From Wade and Zucker, 1970c.)


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brain bundle, whereas Wade and Zucker found no evidence for positive sites in the lateral hypothalamus-medial forebrain bundle complex. It is not inconceivable that the wider distribution of facilitatory sites found by Colvin and Sawyer could be due to intracerebral diffusion of the estradiol. In their experiment, the estradiol benzoate was distributed over a wider surface area (bilateral 23-gauge cannulas) than in the Wade and Zucker work (unilateral 27-gauge cannulas). The 6-day latency reported by Colvin and Sawyer (versus less than 24 hours in the Wade and Zucker) to increase activity might represent the time needed for the estradiol to diffuse t o a site of action. However, this latter hypothesis is not supported by the abundance of ineffective placements in the ventromedial hypothalamic area, which is closer t o the medial preoptic area than many of the effective loci. There are some additional data that may suggest that estradiol acts on a relatively restricted area, perhaps the medial preoptic area (or rostral basal hypothalamus), to enhance activity. First, autoradiographic experiments indicate that the medial preoptic area has a relatively high density of estradiolconcentrating neurons, whereas the medial forebrain bundle generally does not (Pfaff and Keiner, 1973). Second, Kennedy (1964) reported that lesions restricted to the rostral hypothalamus, selectively abolished estradiol-induced running, which should not happen if the estradiol acts on a wide variety of neural loci. Third, Stem and Jankowiak (1972) have found that bilateral actinomycin D implants restricted to the anterior hypothalamus-preoptic area prevented the increase in activity which normally follows systemic estradiol injection with no evidence of general toxicity to the animals (Fig. 8). Although these data seem t o be consistent with the notion of a rather restricted site of

11 11111111111 4 8 I2162024283236404448 Days

FIG. 8. Running wheel activity of ovariectomized female rats given systemic injections o f 15 clg estradiol benzoate (EB)/day. Half of the rats (X) had actinomycin D implanted in the anterior hypothalamus-preoptic area on days 25-34 and the cocoa butter vehicle on days 35-45. The other half (0) had cocoa butter implanted on days 25-34 and actinomycin D o n days 35-45. (From Stern and Jankowiak, 1972.)

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action for estradiol, they are by no means conclusive, and clarification of this point awaits further experimentation. One point that clearly emerges from these lesion and chemical stimulation studies is that the highly correlated changes in eating, running wheel activity, and sexual receptivity cited previously cannot be due to hormone action on a common neural substrate as was suggested by Rothchild (1967) and others. Estradiol placements that stimulated activity had no effect on appetite; placements inhibiting food intake had n o effect on running; and none of the placements induced lordosis (Wade and Zucker, 1 9 7 0 ~ ) I. n addition, although medial preoptic estradiol implants have been reported to stimulate both running and sexual receptivity (Lisk, 1962), lesions in this area abolish estradiol-induced running (Kennedy, 1964) but facilitate induction of sexual receptivity (Powers and Valenstein, 1972b). Thus, although these behaviors are highly coordinated during a variety of reproductive conditions, these fluctuations are almost certainly due to hormonal actions on separate neural substrates. Finally, these data are not consistent with the competing behavior models sometimes invoked t o explain the pattern of behavioral changes at proestrus. For example, it has been suggested that proestrous rats eat less because they are “busy” running or copulating; nor can changes in one behavior merely be a consequence of changes in another (e.g., females lose their appetite because of “arousal” or “sexual excitement”). I t is quite clear that the various behaviors characteristic of proestrous rats can be manipulated independently. The finding that estradiol benzoate placement in the vicinity of the ventromedial hypothalamus decreases eating and body weight (Beatty et ul., 1974; Jankowiak and Stern, 1974; Wade and Zucker, 1970c) is particularly intriguing, since it has been known for some time that neurons in or around the ventromedial hypothalamus act to restrain eating and body weight in a variety of species, (e.g., Hoebel, 1971). These data raise the possibility that estradiol exerts its effect on eating by exciting, either directly or indirectly, hypothalamic neurons that normally restrain eating and/or body weight. The anorega of proestrus (or other times of high estradiol availability) could be explained by estrogenic stimulation of the ventromedial hypothalamic area. Conversely, perhaps the overeating after estradiol withdrawal is a result of decreasing ventromedial hypothalamic activity. That is, ovariectomy may be somewhat akin to a small ventromedial hypothalamic lesion. There are some similarities between the effects of ventromedial hypothalamic lesions and ovariectomy on the eating behavior of female rats. After ventromedial lesions, female rats increase their meal size in both the light and dark phases of the daily light cycle, but although the number of meals eaten in the light also rises, there is a slight drop in the frequency of nighttime meals (Balagura and Devenport, 1970). Kenney and Mook (1974) have reported that following ovariectomy rats also eat larger meals in both the light and the dark.


I

22 1

However, whereas all three of their ovariectomized groups decreased their meal frequency at night, two out of the three groups seemed t o eat more frequent meals when the lights were on. Thus, to the extent that comparisons are possible, the meal pattern data are not inconsistent with the possibility that estradiol withdrawal and ventromedial hypothalamic lesions may have a common mode of action. Kenney and Mook (1974) suggest that ovariectomy acts primarily to impair the onset of satiety during a meal. A recent paper by Drewett (1974) indicates that the opposite pattern occurs at proestrus; meal size decreases at the time when eating is reduced. Thus, estradiol withdrawal (ovariectomy) increases meal size, and rising plasma estradiol levels (proestrus) decrease meal size. Another similarity between the effects of ovariectomy and ventromedial hypothalamic lesions on eating is that both are time-limited; that is, rats only overeat for a restricted period of time. The hyperphagia then subsides and weight stabilizes (Fig. 2) (Hoebel and Teitelbaum, 1966; Mook et ul., 1972; Tarttelin and Gorski, 1973; Wade, 1975). (This point will be discussed more fully in Section IV,B.) Not surprisingly, there are several difficulties for the hypothesis that estradiol affects eating via the ventromedial hypothalamus. For example, after ventromedial lesions, rats may be extremely finicky, refusing to eat unpalatable food (Teitelbaum, 1955), but ovariectomy reduces responsiveness to tastes (Wade and Zucker, 1969b, 1970b; Zucker, 1969). This contradiction is easily resolved if it can be assumed that overeating and finickiness are two separate and not causally related aspects of the ventromedial hypothalamic syndrome, as Corbit and Stellar (1964) have suggested. In fact, Margules (1970a,b) has suggested that there are at least two neurochemically distinct systems in the ventromedial hypothalamus: one mediating cues related t o satiety and one mediating responsiveness to tastes. Both systems would be destroyed by lesions, but estradiol withdrawal might have opposite effects on the two systems (increasing eating and decreasing taste responsiveness). Perhaps the greatest difficulty for the hypothesis that estradiol acts on the ventromedial hypothalamus to depress eating and body weight are the several published (Beatty et al., 1975; King and Cox, 1973; Montemurro, 1971) and unpublished (Finger and Mook, 1971; Kennedy, 1969) reports that systemic injections of estradiol benzoate or diethylstilbestrol depress eating and/or body weight in rats and/or mice with ventromedial hypothalamic lesions. Of course, if the ventromedial hypothalamus were the only target site for estradiol, lesions of this region should abolish the appetite- and body weight-depressing actions of estradiol, but they do not. These data suggest that estradiol can act on other brain loci to affect eating and raise some question as to whether estradiol normally acts via the ventromedial hypothalamus at all (King and Cox, 1973). Both King and Cox (1973) and Beatty et ul., (1975) found that ovariectomy increased, whereas estradiol benzoate injections decreased, both eating and body

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weight in rats with ventromedial hypothalamic lesions, indicating that the animals could still respond to estradiol. However, it was clear that the neurologically intact rats demonstrated significantly greater increases in weight gain and food intake after ovariectomy than did the lesioned females (Beatty et al., 1975). Similarly, exogenous estradiol benzoate depressed body weight more in the unlesioned ovariectomized females than in the animals with ventromedial lesions (Beatty etal., 1975, King and Cox, 1973). The exogenous estradiol benzoate also depressed eating more in the intact than in the lesioned females, but this difference fell short of statistical significance (Beatty e f ul., 1975). Finally, an abstract by Nance and Gorski (1973) suggests that under some circumstances, ventromedial hypothalamic lesions can completely abolish the effects of estradiol benzoate on both eating and body weight in ovariectomized rats. Thus, ventromedial hypothalamic lesions appear to attenuate the effects of estradiol on eating and body weight even though they may not completely abolish the effects. (See Beatty et ul., 1975, for an informative discussion of this work.) One shortcoming of many of these reports is the absence of a detailed histological analysis of the lesions. Our own data (Portnoy, Wade, Ralph, and Balagura, 1973 unpublished data) indicate that if lesions of varying sizes are made in the ventromedial hypothalamus of ovariectomized rats, the rats with the larger lesions are substantially less responsive to estradiol than the rats with smaller lesions. Therefore, hypothalamic lesion size may be a crucial variable in any attempts to alter responsiveness t o hormones with brain lesions. From these results it seems reasonable to conclude that while the ventromedial hypothalamus may not be the site of action of estradiol to depress eating and body weight, it is very likely that the ventromedial hypothalamus is a site of estradiol action. Actually, it is not surprising that estradiol could act at other neural loci, since a wide variety of brain regions have been reported to take up and retain radioactive estradiol as well as affect eating behaviors and body weight. Some obvious examples include corticomedial amygdala, septa1 area, and the olfactory bulbs (Larue and LeMagnen, 1970; Pfaff and Keiner, 1973; Singh and Meyer, 1968; White and Fisher, 1969). However, the medial amygdala probably is not a crucial site of estradiol action on eating and body weight. Powers (1969 unpublished data) found that estradiol benzoate implanted in this region in either satiated or food-deprived ovariectomized rats was without effect on eating. Similarly, corticomedial amygdala lesions do not appear to abolish responsiveness to estradiol in ovariectomized rats (Cox and King, 1974). Additional hormone implant studies will be necessary t o specify just where estradiol can act in the brain to affect eating behavior. It is not surprising that estradiol may act on several neural loci to affect eating, since it appears that there might be other brain areas (as yet largely unspecified) outside the ventromedial hypothalamus that act to restrain eating


223

and body weight. Following ventromedial hypothalamic lesions, rats do not overeat and gain weight indefinitely; eventually both eating and weight gain return to prelesion levels (Hoebel and Teitelbaum, 1966). Some other brain area(s) might be restraining body weight; perhaps estradiol acts on the other brain area(s) that take over some of the functions of the ventromedial hypo thalamus. Although some progress has been made in specifying where estradiol might act to stimulate voluntary exercise and inhibit food intake, very little progress has been made in identifying the output pathways connecting these estradiolsensitive neurons to the “final common pathways” for the behaviors. From Kennedy’s (1964) work, it seems as though estrogenic excitation of the rostra1 diencephalon stimulates activity via the ventromedial hypothalamus. Where the pathway leads from there is not clear. It probably does not depend on connections between the ventromedial hypothalamus and the lateral hypothalamus, since bilateral knife cuts between these two regions cause no permanent changes in the voluntary exercise of female rats (Sclafani, 1971). Similarly, the integrity of the lateral hypothalamus cannot be critical for estrogenic effects on eating, since ovaries seem to restrain body weight just as effectively in rats that have “recovered” from lateral hypothalamic damage as they do in neurologically intact females (Harrell and Balagura, 1975). Additional experiments utilizing selective brain lesions or knife cuts, such as those of Kennedy and Mitra, of Gold, and of Sclafani, could be very helpful in mapping these pathways. Although estradiol can act on the brain to alter energy balance-controlling behaviors, this certainly does not exclude the possibility that ovarian steroids might act on nonneural target tissues t o affect body weight regulation. It is clear that estradiol can alter secretion of anterior pituitary hormones and, thus, the secretions of their target glands. (Coyne and Kitay, 1969; D’Angelo and Fisher, 1969; McCann et al., 1968). It is also clear that pituitary and target gland hormones have important effects on behavioral regulation of body weight (Kennedy and Mitra, 1963a; Pfaff, 1969; Richter, 1956; Stem, 1970; Stevenson and Franklin, 1970; Wade, 1974). However, although it is possible that fluctuations in anterior pituitary function may contribute to the behavioral effects of estradiol, the anterior pituitary is not essential for these effects. Wade and Zucker (1970a; Wade, 1974) found that estradiol benzoate depressed eating in ovariectomized-hypophysectomized weanling rats, and Stern and Jankowiak (1973) found that estradiol benzoate also stimulated running wheel activity in ovariectomized-hypophysectomized adult rats. Therefore, estradiol can still modulate eating and voluntary exercise in the absence of the pituitary gland. Although the anterior pituitary may not be necessary for gonadal effects on behavioral regulation of energy balance (which is the subject of this review), it would be a serious mistake to underestimate the contribution of physiologicalmetabolic factors in gonadal effects on body weight. In fact, sometimes ovarian

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hormones alter the body weight of rats with no apparent effect on behavior. In weanling rats, estradiol and progesterone may lower and raise body weight, respectively, without affecting food intake (Ross and Zucker, 1974; Wade, 1974; Zucker, 1972). We have also found that, if rats are kept in warm environments (around 80°F), they do not overeat following ovariectomy, but they d o gain more weight than intact controls. However, they do.seem to take longer to gain the weight than rats in cooler environments that d o overeat (Portnoy and Wade, 1972 unpublished data). On the other hand, the behavioral changes induced by hormone treatments are not necessarily sufficient to alter body weight by themselves. Roy has compared body weights of three groups of ovariectomized rats: one group given oil injections and ad libitum access t o food; one group given estradiol benzoate injections and ad libitum food; and a final group given oil injections but pair-fed with the estradiol-treated animals. The estradiol-injected group reduced their food intake and lost weight, but the pair-fed, oil-treated rats did not lose any weight, in spite of their restricted food ration. It is apparent that, although behavioral changes undoubtedly contribute to the fluctuations in body weight during various reproductive states, the behavioral changes, in and of themselves, are likely neither necessary nor sufficient to affect body weight. The widespread metabolic effects of gonadal steroids (Aschkenasy, 1959; Salhanic et ul., 1969) are not to be underestimated. Thus far nothing has been mentioned about the neural site of action of progesterone or about where any of the gonadal steroids might act to affect thermoregulation-this is not simply an oversight. With the exception of the report by Jankowiak and Stern (1974) that dorsomedial hypothalamic progesterone implants increase food intake, virtually nothing is known about these problems. It has been suggested (Wade, 1972) that, since the medial preoptic area contains a high density of estradiol-concentrating neurons (F'faff and Keiner, 1973) and is an important neural region for physiological and behavioral thermoregulation (Corbit, 1970; Gale, 1973), perhaps this is a site where ovarian steroids may act to affect thermoregulation. Recent attempts to test this hypothesis have yielded generally negative results. Estradiol implanted in the preoptic area of ovariectomized rats had no effect on rectal temperatures, but there was some suggestion that progesterone implants in this region might raise colonic temperatures (Marrone e f al., 1974). In summary, estradiol may act on a relatively restricted region in the basal anterior diencephalon to stimulate voluntary exercise without affecting other estradioldependent behaviors. Estradiol may act on the area of the ventromedial hypothalamus (and perhaps on the other as yet unspecified brain sites that are functionally similar to the ventromedial hypothalamus) to depress food intake without affecting other estradioldependent behaviors. Because of certain similarities between the eating behaviors of rats following ovariectomy or ventromedial hypothalamic lesions, it was further suggested that, so far as eating


225

behavior is concerned, estradiol withdrawal may be somewhat akin to a small reversible lesion of the ventromedial h y p o t h a l a m u ~ . ~ B.

MECHANISM OF ACTION: A LIPOSTATIC HYPOTHESIS

Experiments demonstrating that estradiol implanted in the diencephalon stimulates exercise and reduces eating in ovariectomized rats independent of the adenohypophysis could indicate that ovarian steroids act directly on neurons that are part of the neural systems controlling regulatory behaviors and that these regulatory behaviors then alter body weight. However, an alternative hypothesis has recently been advanced which may provide a more adequate explanation of a variety of data. Separate laboratories have suggested independently, and nearly simultaneously, that ovarian steroids do not affect regulatory behaviors directly, but, rather, they may act on the brain to alter the set-point about which body weight is regulated (Mook etal., 1972; Wade, 1972). The changes in behavior are seen as attempts to bring body weight into line with this new set-point. A variety of data consistent with this view have subsequently been published. The effects of hormone withdrawal or replacement on food intake are transient, lasting only until a new body weight is reached, but the effects on body weight are permanent, lasting as long as the animal's hormonal condition is held constant. For example, after ovariectomy, rats overeat and gain weight, but after several weeks the hyperphagia and accelerated weight gain subside (see Fig. 2). Food intake then does not differ significantly from preovariectomy levels, although body weight may remain 20-25% above that of intact controls (Mook etal., 1972; Tarttelin and Gorski, 1973). Treatment of ovariectomized rats with estradiol benzoate reverses this pattern; rats undereat until body weight drops to 3Although the role of the ventromedial hypothalamus in estrogenic control of eating and body weight has been stressed, I do not want to place undue emphasis on this brain region, since it is abundantly clear that the ventromedial hypothalamus is but a part of a widely distributed neural regulatory system (cf. Grossman, 1968). It has been suggested that the hyperphagia and obesity following ventromedial hypothalamic lesions may be due to damage t o the ventral noradrenergic bundle passing through this region rather than damage to the ventromedial nucleus per se (Ahlskog and Hoebel, 1973;Gold, 1973). The hyperphagia and obesity induced by ventral bundle lesions are prevented by hypophysectomy, but removal of the pituitary gland has no effect on these changes after electrolytic lesions of the ventromedial hypothalamus (Ahlskog et al., 1974; Valenstein el al., 1969). This finding has two important implications. First, it implies that there is more than one hypothalamic system restraining eating and body weight. Also, it suggests that estrogenic suppression of eating and body weight is probably not mediated by the ventral noradrenergic bundle, since estradiol affects these measures in hypophysectomized rats (Wade, 1974; Wade and Zucker, 1970a). In any event, the important point is that, although the ventromedial hypothalamus is only a portion of the neural weight-regulating system, it is probably one of the parts of this system where estradiol acts to influence eating behavior and body weight.

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preovariectomy levels. In fact, lowering of regulated body weight appears to be proportional to the amount of circulating estradiol, so long as these estradiol titers approximate physiological levels (Wade, 1975) (Fig. 9). Food intake then rises, and body weight levels off at a new lower set-point (Mook et al., 1972; Tarttelin and Gorski, 1973; Wade, 1975) for as long as the estradiol treatment continues. If estradiol treatments are withdrawn, rats respond just as after ovariectomy; a transient hyperphagia causes a permanent elevation of body weight (Wade, 1975) (See Fig. 4). Therefore, estradiol seems t o affect eating behavior by lowering the body weight set-point; estradiol withdrawal appears t o raise body weight set-point. The changes in eating behavior are viewed as being secondary t o altered body weight set-point. Although the effects of hormonal manipulations on eating are transient, lasting only until body weight is realigned, the effects on locomotor activity appear to be permanent. After ovariectomy, rats are permanently hypoactive; activity does not return when body weight stabilizes. Conversely, unlike the hypophagia, the increase in activity after estradiol replacement therapy outlasts the period of weight loss (Mook et d.,1972). Thus, although activity levels are always inversely related t o food intake (see Table I) and undoubtedly contribute t o the fluctuations in body weight, it is likely that estradiol directly stimulates voluntary exercise, and the changes in activity are not a consequence of a shift in body weight set-point. These results are consistent with our report that estradiol acts on separate neural loci to affect eating and exercise (Wade and Zucker, 1970~). The possibility that the primary effect of estradiol is t o lower the body weight set-point is consistent with the hypothesis that a principal site of estradiol action is the ventromedial hypothalamus. For some time, Kennedy (1953, 1967,1969) has maintained that one function of this brain region is to monitor body weight

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FIG. 9. Food intake (top) and body weight (bottom) of ovariectomized rats injected with 0.5, 2.0, and 5.0 /.fg estradiol benzoate (EB)/day or with sesame oil vehicle. Injections were given from day 7 through day 30. (From Wade, 1975 .)


227

(or fat content) and to adjust feeding behavior so that body fat levels are maintained within a restricted range. This lipostatic theory suggests, “It is apparent that the ventromedial nucleus in the normal rat restrains the accumulation of surplus fat independently of any possibly existing central control of the lean body mass” (Kennedy, 1969). This lipostatic interpretation of ventromedial hypothalamic function is supported by a variety of data. Perhaps the most convincing is the work of Hoebel and Teitelbaum (1966). Following ventromedial hypothalamic lesions rats overeat only until a certain amount of weight is gained; then the hyperphagia subsides, and the growth curve is parallel to, but higher than, that of intact rats. If the obese rats are starved until they reach their prelesion bod) weights, the hyperphagia is reinstated when ad libitum feeding is resumed but lasts only until the obesity is restored. Conversely, if the obese rats are made “superobese” by daily force feeding, they voluntarily undereat (once the force feeding is terminated) until they return to their obese set-point. Finally, if neurologically intact rats are made obese before lesioning, they are not hyperphagic following brain damage. Thus, rats with ventromedial hypothalamic lesions seem to be perfectly capable of regulating their body weights; they merely regulate at a higher weight level (or body fat content) than unlesioned rats. The ventromedial hypothalamic lesion seems to raise the body weight set-point, and the rats overeat in order to align body weight with this new set-poin t . The several similarities between the eating behaviors of ovariectomized and ventromedial hypothalamic-lesioned rats have already been mentioned. Perhaps, then, estradiol acts on the ventromedial hypothalamic lipostat to lower the regulated body weight. Consistent with this possibility are the changes in carcass composition that follow manipulation of gonadal hormones in female rats. The increase in body weight following ovariectomy or progesterone treatment is mainly due t o increased fat deposition. As discussed previously, these two treatments produce similar and nonadditive effects on body weight and composition (Galletti and Klopper, 1964; Hervey and Hervey, 1966, 1967; Leshner and Collier, 1973). During pregnancy there is an increase in carcass fat content, similar t o that during progesterone treatment (Hervey et al., 1967). Finally, Kennedy (1969) has suggested that the principal source of weight loss during estradiol treatment is lipolysis. Thus, ovarian hormones, like the ventromedial hypothalamus, seem to be of some importance for the regulation of the body’s fat stores. As Mook et al. (1972) point out, it is important to note that, whereas blood estradiol levels may dictate a particular body weight level, they can do SO o d y within certain limits. Even though rats overeat and gain weight after either ovariectomy or ventromedial hypothalamic lesions, the changes in these measures following ovariectomy are relatively modest compared with the effects of the lesions. After ventromedial hypothalamic lesions, a doubling of body weight is not uncommon, but the body weight of ovariectomized rats rarely increases

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by more than 25-30%. There seems to be an upper limit beyond which body weight cannot shift following just ovarian steroid withdrawal. Conversely, there seems t o be a lower body weight limit below which body weight cannot be forced by estradiol treatment. Neither reasonable (3 pg/day) (Tartellin and Gorski, 1973) nor unreasonable (200 &day) (Hervey and Hervey, 1965) doses of estradiol benzoate will force body weight significantly below that of untreated intact female rats. Nor does estradiol treatment affect eating and body weight of ovariectomized rats that are already regulating at a low body weight because of prior adrenalectomy (Redick e t a l . , 1973) or because of neonatal underfeeding (Zucker, 1972). Redick et ul. (1973) have shown that estradiol treatment will decrease both eating and body weight in ovariectomized-adrenalectomized rats that have been made mildly obese by giving them an especially attractive diet. They conclude by suggesting‘ that “estradiol suppresses feeding only in the face of actual or impending obesity. It probably affects the system(s) concerned with the long-term regulation of body weight; but it does not act directly on the mechanisms which mobilize or inhibit feeding.” Thus, although estradiol could act upon a hypothalamic lipostat to lower body weight set-point, it appears that body weight (or more likely fat content) cannot be driven below that of intact cycling females. Conversely, estradiol withdrawal induces only a limited obesity-no more than a 25-30% rise in body weight. Estradiol may cause only a “fine tuning” of lipostatic regulation. If estradiol alters eating behavior by lowering the neural set-point for body weight, how, then, does progesterone exert its effects on these measures? Because progesterone did not seem to affect eating and body weight in the absence of estradiol (see Section III,B for references), we reasoned that it exerted its appetite- and weight-stimulating actions by acting as an antiestrogen (Wade, 1972; Wade and Zucker, 1969a)-perhaps by inhibiting uptake of estradiol by the brain (Anderson and Greenwald, 1969; Lisk, 1974). It has recently been shown that concurrent injections of progesterone attenuate the effects of estradiol benzoate on eating and body weight (Fig. 10). In fact, if sufficient progesterone is given it can completely block the lowering of body weight set-point by estradiol (Wade, 1975). However, Roberts el ul. (1972) have suggested an alternative interpretation: if estradiol acts directly on the brain to lower body weight set-point, perhaps progesterone also can act on the brain independently of estradiol t o raise body weight set-point. It was suggested that the reason that ovariectomized rats do not respond t o progesterone is because they are already obese; that is, if estradiol cannot depress eating and body weight in already lean rats, perhaps progesterone cannot raise weight above the obesity induced by ovariectomy. Roberts et ul. (1972) tested their hypothesis by treating ovariectomizedadrenalectomized rats with progesterone and observing the effects on eating and

229


body weight. This preparation is particularly appropriate for this sort of experiment since it has been shown that adrenalectomy either prevents or reverses the effects of ovariectomy on body weight (Grunt, 1964; Mook et al., 1972; Stem et al., 1974). They found that treatment of ovariectomized-adrenalectomized rats with 5.0 mg progesteronelday caused a significant increase in food intake and body weight (Roberts et al., 1972). In this preparation there is, of course, no circulating estradiol, so that the progesterone could not be affecting energy balance by antagonizing the actions of estradiol. This finding has recently been replicated (Ross and Zucker, 1974). It was also shown that the rapid weight gain during progesterone treatment was transient; body weights plateau parallel to, but higher than, oil-treated controls, suggesting that progesterone was directly raising body weight set-point. Roberts et al. noted that treatments that restore responsiveness to progesterone in ovariectomized rats (adrenalectomy or estradiol treatment) all prevent the usual postovariectomy obesity. Perhaps, then, progesterone does directly raise body weight set-point (independent of estradiol), but only in the absence of a preoccurring weight gain. One difficulty with the work in ovariectomized-adrenalectomized rats is the extremely high dose (5.0 mg/day) of progesterone that has been used (Roberts et al., 1972; Ross and Zucker, 1974). This is approximately 20 times the dose of progesterone reported to facilitate lordosis in 100%of ovariectomized estradiolprimed rats (Powers and Valenstein, 1972a). Therefore, it is difficult to determine whether the effects of progesterone on eating and body weight in ovariectomized-adrenalectomized rats are of any physiological significance or whether they are merely artifacts of unusually high progesterone doses. If the absence of a preoccurring weight gain is all that is necessary to induce responsiveness to progesterone in ovariectomized rats, then the method used to

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FIG. 10. Food intake (top) and body weight (bottom) of ovariectomized rats injected with sesame oil vehicle, 2.0 pg estradiol benzoate (EB)/day, or with estradiol benzoate plus 0.5, 1.0, or 2.0 mg progesterone @)/day. Injections were given from day 7 through day 30. (From Wade, 1975.)

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prevent the weight gain (adrenalectomy or estradiol treatment) should not affect the rats’ responsiveness to exogenous progesterone. If, on the other hand, the principal action of progesterone is to interfere with the actions of estradiol, then estradiol-treated ovariectomized rats might be more responsive to progesterone than ovariectomized-adrenalectomized rats. This possibility was recently tested in an experiment in which the effects of several doses of progesterone on eating and body weight were compared in two groups of rats whose postovariectomy weight gain was prevented either by concurrent adrenalectomy or by daily injections of 2.0 pg estradiol benzoate (Wade, 1975). It was clear that the estradiol-treated rats were more responsive to the progesterone than those that were adrenalectomized. Less than 0.5 rng progesterone/ day significantly increased eating and body weight in the ovariectomized, estradiol-treated females, whereas progesterone doses of less than 5 .O mg/day were without effect on either measure in the ovariectomized-adrenalectomized rats (Wade, 1975). Therefore, the antiestrogenic effects of progesterone are clearly evident with plasma hormone titers far below those necessary to stimulate eating and weight gain in the absence of estradiol. This work seems to indicate that the principal action of progesterone on energy balance-regulating behaviors is to decrease estradiol availability or effectiveness in the central nervous system. Although these data do not rule out the possibility that endogenous progesterone could possibly directly raise the body weight set-point under certain circumstances, the extremely high dosages necessary to elicit this effect suggest that it may occur only during times of very high progesterone secretion, such as during late pregnancy (Hashimoto et al., 1968). However, even during pregnancy it is not clear whether the overeating and obesity are due to the high plasma progesterone titers, the very low levels of circulating estradiol (Yoshinaga et al., 1969), or both. Ross and Zucker (1974) have recently suggested an alternative interpretation of the effects of progesterone on ovariectomized-adrenalectomized rats. They indicate that progesterone might mimic the effects of adrenal corticosteroids and permissively increase the food intake of adrenalectomized rats simply by improving their general health. They point out that progesterone, which restores the weight gains of ovariectomized-adrenalectomized rats to levels characteristic of ovariectomized females, is effective in prolonging the survival of adrenalectomized rats (Greene et al., 1939). Relevant to this point are the reports that adrenocorticosteroids (like progesterone) also permit normal weight gain in ovariect omized-adrenalec tomize d females (Rodie r , 1973; Tarttelin and Gorski , 1973). On the other hand, in nonadrenalectomized rats, exogenous corticosterone only depresses eating and body weight (Stevenson and Franklin, 1970). We have also found that progesterone stimulates running wheel activity in ovariectomized-adrenalectomized rats (Fig. 11) (Marrone et al., 1975), just as corticosterone does in adrenalectomized males (Leshner, 1971). This activity-

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Progesterone could exert its adrenocorticosteroid-like effects by being converted to a corticosteroid by extra-adrenal enzymes (it is a precursor of the adrenal hormones) or by acting directly as a weak adrenocorticoid. It is known, for example, that corticosterone can substitute for progesterone in facilitating lordosis more effectively than the progesterone metabolite, Sa-pregnane-3,20dione, in guinea pigs (Wade and Feder, 1972b). These data certainly raise the possibility that “the increases in eating and body weight [progesterone] produces may, therefore, reflect generally improved health and not specific changes in the central energy balance system” (Ross and Zucker, 1974). The only data I am aware of that may be inconsistent with this possibility is the report by Jankowiak and Stern (1974) that progesterone implanted in the dorsomedial hypothalamus of ovariectomized-adrenalectomized rats stimulates eating and weight gain. Unless there is substantial systemic leakage of the progesterone from the implants, it is not obvious how this treatment could be improving the animals’ general health. Perhaps a better way to test the Roberts etal. hypothesis would be to find another way to prevent the postovariectomy obesity than by adrenalectomy and then inject progesterone. Possibly rats that have been undernourished during infancy would be appropriate, since they d o not seem to become obese after adult ovariectomy (Zucker, 1972). Another interesting implication of the Ross and Zucker work is that progesterone may be able to block the peripheral metabolic actions of estradiol independently of its antiestrogenic effects on behavior. Hervey and Hervey (1966b) reported that progesterone increased body weight in intact rats even when they were pair-fed with vehicle-treated controls, but Ross and Zucker (1974) were unable to find any evidence for a weight-promoting effect of progesterone in ovariectomized rats pair-fed with oil-treated controls. An obvious interpretation of these divergent results is that progesterone can attenuate the metabolic effects of ovarian estradiol in intact females in the absence of any effects on eating. Thus, estradiol may affect eating behavior indirectly by acting on the brain (perhaps the ventromedial hypothalamus) to lower the set-point about which body weight (or fat content) is regulated in a dose-dependent fashion. Withdrawal of estradiol, by any means, raises body weight set-point. Progesterone can attenuate or completely block the set-point lowering effects of estradiol, again in a dose-dependent fashon, perhaps by decreasing the availability or effectiveness of estradiol in crucial brain sites. It has also been suggested that progesterone might directly raise body weight set-point independent of its antiestrogenic actions, but this effect is somewhat more difficult to elicit and may be due to nonspecific actions of pharmacological doses of progesterone. The possibility that estradiol acts on the brain t o lower body weight set-point has a very exciting implication if i t can be assumed that this effect is not limited to laboratory rats, an assumption that is not without justification (see Section VIII). That overweight is a persistent and pervasive health problem in many societies goes without question (Balagura, 1973; Mayer, 1969), and an especially


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impressive aspect of much of this obesity is its resistance to any form of permanent treatment. The long-term prognosis for m y “cure” for obesity has been exceptionally discouraging. Recently, Nisbett (1972) has advanced an hypothesis which may in part account for this impressive lack of success in treating human obesity. He suggests that many persons are biologically programmed t o be obese; because of either a genetic predisposition to overweight or, because of overnutrition during early development, their brains defend a higher body weight set-point than lean persons. If this is, in fact, the case, treatments of the symptoms of obesity (overeating, underactivity, inappropriate meal patterns, etc.) are ultimately destined to failure if body weight set-point remains elevated. On the other hand, an ideal (and seemingly painless) treatment would be one that lowers the neural set-point for body weight; then the appropriate behavioral adjustments should follow naturally and voluntarily. The problem, of course, is finding a treatment that lowers body weight setpoint. If estradiol acts in human beings to lower set-point as it does in rats, then it could be used for weight control. An estrogenic weight-reducing compound could be especially useful, since the effectiveness of estradiol in depressing food intake and in dictating a low body weight in rats seems to be independent of diet nutritional value or palatability (Jennings, 1973; Redick and Mook, 1973). However, it is obvious that the widespread physiological actions of estradiol would preclude its use in human beings, especially in men. The only hope for this sort of treatment for obesity would be if there were some way of selectively stimulating the neural estrogen “receptors” that control body weight without stimulating any of the other estrogen-sensitive sites in the body. Intracerebral placement of estradiol would not be an appropriate methods, for several obvious reasons. However, if the neural estrogen “receptor” for weight regulation were t o have some unique property that differentiated it from all other estrogen receptors in the body, it might be possible t o find some chemical that stimulated it (and lowered body weight set-point) without affecting the other estrogen-sensitive systems. That this may, in fact, be the case is suggested by some work examining the effects of some antiestrogens on regulatory behaviors in rats. The nonsteroidal compound, MER-25, is consistently antiestrogenic on a variety of physiological end points in a number of species. In addition, MER-25 appears to have almost no estrogenic, androgenic, antiandrogenic, progestational, antiprogestational, or gonadotropic activities with regard t o these end points (Lerner et al., 1958). Compound MER-25 could exert its antiestrogenic actions by competing with endogenous or exogenous estradiol for target-organ receptor sites (Jensen et d.,1972). Similarly, MER-25 seems to be antiestrogenic toward behaviors, since it can block estradiol-induced sexual receptivity (Meyerson and Lindstrom, 1968) and locomotor activity (Roy and Wade, 1975a). In contrast to its nearly pure antiestrogenic effects on other measures,

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MER-25 appears to act as an estrogen on eating and body weight. Injection of male or female gonadectomized rats with MER-25 reduces both eating and body weight. Just as with estradiol, the effects of MER-25 on eating seem to be transient, but the weight-reducing effects last as long as the MER-25 treatments continue. It is extremely unlikely for several reasons that these appetite- and weight-reducing effects of MER-25 are due to a nonspecific toxicity: (1) the changes in eating are transient, whereas the effect on body weight is lasting; (2) MER-25 does not suppress base-line running wheel activity (in non-estrogentreated rats), nor does it attenuate starvation-induced activity, as it might if the animals were simply ill; (3) concurrent progesterone injections attenuate the effect of MER-25 on eating and body weight, just as they do with estradiol; (4) implants of MER-25 in the ventromedial hypothalamus depress eating in ovariectomized rats, just as estradiol does; (5) we have been unable to establish conditioned gustatory aversions (Garcia e t d . , 1974) using MER-25 as the unconditioned stimulus; and (6) female rats appear to be more responsive to MER-25 than males (Roy and Wade, 1975b). It is quite possible, therefore, that the neural estrogen “receptor” affecting body weight does differ from other estrogen-sensitive systems in the body: MER-25 is solely estrogenic with regard to body weight regulation but antiestrogenic in other physiological and behavioral systems. These estrogenic actions of MER-25 may be shared by some other steroid antagonists, including the antiandrogen, cyproterone acetate (Vilberg et al., 1974), and the antiestrogen, CI-628 (Powers, 1974 personal communication). It is obvious that compounds such as MER-25 or CI-628 would not be appropriate for weight control, since their antiestrogenic side effects would be just as objectionable in most cases as the estrogenic effects of estradiol. It seems as though an ideal weight-reducing drug would be one that acts on the neural estrogen-sensitive mechanisms to lower body weight set-point but has neither estrogenic nor antiestrogenic effects in other hormone-sensitive systems. I doubt that any such compound exists at the present time. C. INTERACTION WITH BRAIN MONOAMINERGIC SYSTEMS

Although a lipostatic hypothesis is an attractive and convenient way to describe the effects of ovarian steroids on eating and body weight, it is only a description of the data and in and of itself provides little information about how steroids might interact with the brain to affect energy balance. At best, the notion of shifts in body weight set-point helps to bring some order to our thinking about a variety of phenomena and suggests some reasonable approaches for additional research. At worst, this sort of pseudoexplanation could lead to a false impression that we understand more than we really do and serve to stifle creative research. The distinction between labeling a phenomenon and explaining it should remain clear in our minds.


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Actually, work on the mechanisms of action of steroids in the central nervous system is still in its infancy and lags far behind similar work in hormone-sensitive peripheral tissues (e.g., O’Malley and Means, 1974). In peripheral tissues there is a great deal of evidence suggesting that steroids act on the genome to alter genetic transcription. To the extent that comparisons are possible, it is not inconceivable that ovarian hormones have a similar mechanism of action in the brain. An extensive discussion of the neurochemical actions of steroids is beyond the scope of this paper, but the interested reader is referred to several excellent recent reviews (McEwen ef ul., 1970, 1972, 1974). One very exciting possibility is that steroids might affect behavior by altering the synthesis or activity of one (or more) of the several monoamines hypothesized to serve as neurotransmitters in the central nervous system. Indeed, although the current literature is somewhat confusing and controversial, it seems clear that ovarian hormones d o alter brain monoamine metabolism, particularly that ofnorepinephrine (Anton-Tay and Wurtman, 1971; Wurtman, 1971). It has been apparent for some time that manipulation of hypothalamic noradrenergic activity has very striking effects on eating behavior of rats (see Hoebel, 1971, for a particularly cogent review). One current theory suggests that there are cY-adrenergic-receptive cells in the perifornical and medial hypothalamus (highest density in the paraventricular nucleus) where norepinephrine acts to enhance eating behavior. Opposing this (Y feeding system are padrenergicreceptive cells in the perifomical and lateral hypothalamus where norepinephrine acts t o inhibit food intake (Leibowitz, 1972). This is a very attractive theory, with many data supporting it, and it is easy to imagine how estradiol might inhibit food intake by either inhibiting the a-adrenergic “feeding” system or by stimulating the 0-adrenergic “satiety” system. However attractive it may be, this model has not gone without challenge. Margules (1970a) has suggested that ceadrenergic agonists inhibit, rather than facilitate, food intake when placed in the medial hypothalamus. Furthermore, whether a-adrenergic agonists stimulate or inhibit eating may vary as a function of the light-dark cycle (Margules etul., 1972). Clearly, the action of norepinephrine on feeding behavior is far from simple. As indicated above, ovarian hormones do affect hypothalamic norepinephrine metabolism. During the estrous cycle, anterior hypothalamic norepinephrine varies cyclically. At proestrus the absolute level of norepinephrine is high; it drops just after ovulation to its lowest values on the day of estrus; and it rises again during metestrus and diestrus (Stefano and Donoso, 1967). After ovariectomy there is an increase in absolute levels, synthesis, and turnover of hypothalamic norepinephrine (Anton-Tay ef al., 1969, 1970; Anton-Tay and Wurtman, 1968; Bapna el ul., 1971; Donoso and Stefano, 1965). These effects of ovariectomy can be reversed by huge doses of estradiol benzoate and progesterone. Two recent experiments have attempted to integrate this information and indicate how estradiol acts on the brain to alter noradrenergic activity and, thus,

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eating behavior (Simpson and DiCara, 1973; Stern and Zwick, 1973). Unfortunately, they arrive at opposite conclusions. Simpson and DiCara (1 973) suggest that high blood titers of estradiol inhibit eating by decreasing levels of hypothalamic dopamine-0-hydroxylase, the enzyme that catalyzes the synthesis of norepinephrine from dopamine. They find that noradrenergic stimulation of the anterior hypothalamus increases food intake of female rats regardless of blood estradiol levels (estrus, diestrus, ovariectomized with and without estradiol replacement), but that dopaminergic stimulation increases eating only in the absence of high estradiol levels (diestrus and ovariectomized without estradiol replacement). They speculate that estradiol inhibits the dopamine-to-norepinephrine conversion, and, thus, eating behavior. However, this theory would seem to have some difficulty accounting for the increased eating at estrus relative to proestrus, since hypothalamic norepinephrine is higher at proestrus (Stefan0 and Donoso, 1967). Stem and Zwick (1973) suggest essentially the opposite hypothesis, that is, increased brain norepinephrine inhibits eating and stimulates activity. They found that intraventricular injections of either 1 fig estradiol benzoate or large doses of norepinephrine (100-250 pg) inhibited eating and stimulated activity of ovariectomized rats in the dark. In addition, they report that phentolamine, an a-adrenergic antagonist, attenuated and imipramine, which blocks norepinephrine reuptake, enhanced the effects of both the estradiol and norepinephrine on activity. In agreement with Margules er d.,(1972), they suggest that high hypothalamic norepinephrine inhibits food intake. But, then, why does ovariectomy increase both eating and hypothalamic norepinephrine? Given the multitude of potential pitfalls along the way, it is little wonder that no consensus has arisen from the attempts to correlate blood estradiol levels with hypothalamic norepinephrine and eating behavior. First, the functional significance of the changes in hypothalamic norepinephrine levels and turnover with changes in steroid secretion are not really clear. Do increased brain levels indicate enhanced synthesis and activity or decreased release and activity? Does increased turnover indicate an increase in synaptic release and activity or merely an increase of intracellular metabolism independent of synaptic release? Second, the anatomical resolution in most of the studies correlating steroids and brain monoamines is really inadequate for any conclusions about specific behaviors. Typically, no more than two or three pieces of hypothalamus are examined, even though anatomically overlapping monoaminergic neurons in any one of these areas may affect a variety of functions including eating, activity, thermoregulation, estrous behavior, and control of hypothalamic releasing hormones. There is no way of knowing which of these functions is being affected by the monoamine fluctuations. Finally, just how norepinephrine affects eating behavior has not yet been resolved. Whether norepinephrine increases or decreases eating depends on a variety of factors including anatomical locus, stage of the light-dark cycle, and the investigator.


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V. DEVELOPMENT OF RESPONSIVENESS TO OVARIAN STEROIDS AND EFFECTS OF LACTATION In a number of ways the behavior of prepubertal female rats resembles that of estradiol-deprived (ovariectomized, pregnant, or pseudopregnant) adult females. Weanling females are almost completely inactive in running wheels (Kennedy and Mitra, 1963b). These animals are able to run, since it has been shown that they increase their activity when food-deprived (Gentry and Wade, 1973 unpublished data; Kennedy, 1964); they simply choose not t o exercise. At the time of puberty activity increases. Prepubertal females, like estradiol-deprived adults, are hyperphagic. In fact, if eating is computed on a body weight basis, weanlings eat nearly twice as much as adults (Kennedy, 1957). Immature rats also build larger nests and gain weight more rapidly than sexually mature rats (Kinder, 1927; Slob, 1972). Around puberty eating, nest-building, and weight gain drop gradually. The simplest explanation for the similarities between weanling and estradioldeprived adults, of course, would be that the prepubertal ovary secretes insufficient estradiol to affect behavior and restrain body weight. However, Weisz and Gunsalus (1973) suggest that prepubertal female rats have higher plasma estradiol levels than adults do. An alternative (and not mutually exclusive) hypothesis is that the estradiol-sensitive neurons in the brain are not sufficiently mature t o respond to estradiol. This latter hypothesis is not likely to be correct for several reasons. Plapinger and McEwen (1973; Plapinger, McEwen, and Clemens, 1973) have reported that the hypothalamic cytoplasmic and nuclear estradiol-binding systems are mature well before puberty. Also, it is likely that the hypothalamic neurons controlling the adenohypophysis are hypersensitive to estradiol before puberty (Ramirez and McCann, 1963; Smith and Davidson, 1968). A third possibility is that whether or not the prepubertal ovary is secreting any estradiol, perhaps some other hormone or metabolic factor is interfering with neural responsiveness to estradiol. The preponderance of the available data is consistent with this third possibility. Ovarian hormones d o not restrain eating or body weight prepubertally. Ovariectomy at birth or at the time of weaning does not affect either measure until the time intact controls reach puberty. Then the ovariectomized animals eat and weigh more than the intacts (Grunt, 1964; Slob, 1972; Wade and Zucker, 1970a). However, there is no particular significance t o the relation between puberty and ovarian restraint of body weight, since induction of precocious puberty does not cause a precocious slowing of growth (Wade and Zucker, 1970a). This is an important point indicating that the neural changes causing puberty and a slowing of growth are not causally related. Rather, i t is likely that both effects are caused by a third factor-attainment of a certain minimum body weight (see below).

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The neural mechanisms controlling eating and body weight to not respond to exogenous hormones prepubertally. Injection of ovariectomized rats with suprathreshold doses (for adults) of estradiol benzoate does not suppress eating until approximately 40 days of age (Fig. 12). This is about the same time ovarian estradiol first restrains eating in intact females (Wade and Zucker, 1970a). Similarly, progesterone injections do not stimulate food intake in intact weanlings as they do in adults (Ross and Zucker, 1974). This makes sense: if estradiol does not restrain eating, progesterone cannot block its effects. However, estradiol and progesterone do affect body weight in weanlings, to some extent. Estradiol benzoate depresses body weight before i t has any effect on eating, and progesterone increases weight gain in intact weanlings without affecting eating (Ross and Zucker, 1974; Wade, 1974; Zucker, 1972). These effects are relatively modest when compared to the effects seen in adults, and they very likely represent direct effects of the steroids on metabolic processes cited previously. In addition, the effect of prepubertal estradiol on body weight may not be reversible (Wade, 1969 unpublished data). Why doesn’t estradiol inhibit food intake in weanlings as it does in adults? We have suggested previously that the ventromedial hypothalamus does not restrain eating and weight gain in immature rats. If estradiol inhibits eating by acting on the ventromedial hypothalamus (or other brain sites restraining body weight), then it should have no effect in an animal with an impotent ventromedial hypothalamus (Wade, 1974; Wade and Zucker, 1970a). Prepubertal rats are hyperphagic (intake computed on a body weight basis), and they eat as much as adults with ventromedial hypothalamic lesions H 0-0 0-0 0-0

SPAYED 0 INTACT8 SPAYED 8 SPAMD $

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FIG. 12. Food intake of immature ovariectomized rats treated with 1.0 ccg estradiol benzoate (EB)/day or with sesame oil vehicle. A group o f intact females treated with the oil vehicle was included for comparison. Duration of treatment is indicated. (From Wade and Zucker, 1970a.)


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(Kennedy, 1957). In addition, neither electrolytic lesions of the ventromedial hypothalamus nor parasaggital knife cuts between the ventromedial and lateral hypothalamus (both of which induce overeating and obesity in adult rats) causes any additional hyperphagia in immature female rats (Bernardis, 1966; Bernardis and Skelton, 1965-1966; Gold and Kapatos, 1975; Kennedy, 1957). This is not simply due to a ceiling effect; weanlings do increase their food intake when placed in the cold (Teitelbaum etul., 1969). Rats lesioned as weanlings d o overeat and outgain unlesioned animals, but only after they reach 7-8 weeks of age, the time the intact females reach puberty (Gold and Kapatos, 1975). Kennedy (1957) has suggested that the postpubertal overeating and weight gain is simply a continuation of the juvenile pattern. Thus, the ventromedial hypothalamus only restrains eating and weight gain postpubertally. It is very likely that pituitary hormones are either directly or indirectly (through their metabolic effects) responsible for the lack of hypothalamic restraint of eating and body weight in immature rats. Hypophysectomy of weanling rats depresses eating and slows growth. Rapid weight gain and hyperphagia can be restored in these hypophysectomized weanling either by ventromedial hypothalamic lesions or by daily injections of growth hormone (Goldman et ul., 1970; Han, 1967; Kurtz etul., 1972), neither of which has any effect in intact weanlings. These effects of ventromedial hypothalamic lesions and growth hormone in immature rats are not additive, suggesting a common mode of action: inhibition of the ventromedial hypothalamus. How does growth hormone inhibit the ventromedial hypothalamus? One obvious possiblity is that growth hormone acts directly on the neurons in this region to inhibit their activity. I am aware of no data bearing directly on this hypothesis, although it is clear that other hormones, such as insulin or estradiol, can act directly on the ventromedial hypothalamus (Debons el ul., 1969; Wade and Zucker, 1 9 7 0 ~ ) .An alternative (and not mutually exclusive) possibility is that growth hormone causes certain metabolic changes that feed back to affect hypothalamic activity. Kennedy (1967, 1969) has suggested that, in the weanling rat, lipostatic regulation by the ventromedial hypothalamus is fully mature. However, because growth hormone stimulates rapid growth of the lean body mass and inhibits lipogenesis, there is little accumulation of body fat. Because there is little body fat in weanling rats, the ventromedial hypothalamic lipostat is not triggered until after puberty when growth slows and body fat begins to accumulate. Thus, growth hormone masks ventromedial hypothalamic restraint of eating by eliminating the normal satiety signals t o the neural lipostat. If this is the case, it is no wonder that estradiol, which only causes a ‘‘fine tuning” of lipostatic regulation (Section IV,B), is not effective in an animal with little body fat. This hypothesis predicts that if hypophysectomy (and increased fat deposition) restore lipostatic control, then estradiol should depress eating in hypophysec-

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tomized weanlings. This is, in fact, the case. Treatment of ovariectomizedhypophysectomized weanlings with a dosage of estradiol benzoate (1 pg/day) that is ineffective in nonhypophysectomized weanlings immediately depressed both eating and body weight (Wade and Zucker, 1970a). If growth hormone is really the pituitary factor responsible for the prepubertal refractoriness to estradiol, then it should be possible to restore the refractoriness in hypophysectomized weanlings with exogenous growth hormone. Again, this is the case. The effects of estradiol benzoate on eating in hypophysectomized-ovariectomized weanling rats were completely blocked by concurrent injections of bovine growth hormone (Wade, 1974). These results raise the question: Why does pituitary growth hormone inhibit responsiveness to estradiol in weanlings but not in adults? It had been suggested previously that growth hormone secretion might decline at about the time estradiol begins to influence food intake (Kurtz etul., 1972; Wade and Zucker, 1970a). More recent evidence indicates that this is clearly not the case: plasma growth hormone levels rise sharply at puberty (Dickerman el ul., 1972). Whether or not plasma growth hormone levels drop, there is a decreasing responsiveness to the actions of growth hormone with increasing age and/or body weight (Emerson, 1955). A reduced metabolic responsiveness to growth hormone, rather than lower plasma levels, could be the reason that adult females respond to estradiol but weanlings do not. To summarize, it is hypothesized that pituitary growth hormone masks lipostatic regulation of eating and body weight in immature rats by abolishing the normal satiety signals to the brain. Because estradiol alters eating by way of this lipostatic mechanism, it is ineffective in weanlings. Hypophysectomy abolishes and growth hormone restores the refractoriness of the neural eating system t o estradiol. The work of Zucker (1972) is consistent with this hypothesis. He reared female rats in litters of 3, 9, or 15 pups. This resulted in rats of a wide range of body weights at weaning. The rats were then divided into three groups of high, medium, and low body weights. They were ovariectomized at 23 days, and half the animals were treated with 1 pg estradiol benzoatelday on days 30-55. Although the three groups exhibited undereating in response to the estradiol at dissimilar ages (the heavier rats responded earlier), hypophagia attributable to the estradiol did occur at a similar body weight in all three groups. Each of the estradiol-treated groups began to eat significantly less than its respective control group when it reached approximately 160 gm. Therefore, it is likely that the attainment of a certain minimum body weight (or body fat content) is a prerequisite for the appetite-suppressing actions of estradiol, rather than the attainment of any particular chronological age (Zucker, 1972). By using the same technique, Kennedy and Mitra (1963b) have shown that puberty also is more closely related to body weight than to chronological age in rats. It is likely, then,


24 1

that puberty and eating responsiveness to estradiol are temporally associated, not because of a causal relation between the two, but because they are both triggered by the attainment of a certain body weight. The refractoriness of the prepubertal neural feeding system is probably restricted to stimuli, such as estradiol, that affect food intake via the lipostatic mechanisms in the ventromedial hypothalamus. Amphetamine, insulin, and environmental temperature all affect eating in prepubertal rats (Lytle et al., 1971; Teitelbaum et al., 1969; Wade and Zucker, 1970a), but none of these stimuli acts via the ventromedial hypothalamus. It is likely that amphetamine and insulin act via the lateral hypothalamus, whereas thermal stimuli act on the anterior hypothalamus-preoptic area to influence eating (Booth, 1968; Carlisle, 1964; Epstein and Teitelbaum, 1967; Hamilton and Brobeck, 1964). The neural system controlling voluntary exercise is also refractory to exogenous estradiol prepubertally. Even very large doses of estradiol benzoate (up to 100 pg/day) do not stimulate wheel running in ovariectomized weanlings (Gentry and Wade, 1974 unpublished data; Kennedy, 1964; Porterfield and Stern, 1974). The refractoriness of the neural exercise system may also be due to the actions of pituitary growth hormone. Porterfield and Stem (1974) report that hypophysectomized-ovariectomized weanlings increase their locomotor activity in response to exogenous estradiol benzoate before intact weanlings do. In addition, this responsiveness to estradiol injections can be delayed by concurrent injections of bovine growth hormone (1 mglday). These results may mean that growth hormone can act directly on the brain to inhibit responsiveness to estradiol independently of any effects on lipostatic mechanisms. Other antagonisms between estradiol and growth hormone have been noted previously (Josimovich et al., 1967; Schwartz et al., 1969). Note, however, that the inhibition of running by growth hormone did not last indefinitely; activity eventually increased in spite of continuing growth hormone treatment (Porterfield and Stern, 1974). We, too, have had little luck in inhibiting estradiol-induced running with growth hormone in adult rats (Gentry and Wade, 1973 unpublished data). Finally, Rothchild (1969) has reported that progesterone does not raise body temperature in prepubertal rats as it does in adults. The physiological basis for this refractoriness to progesterone is, as yet, unspecified. In conclusion, prepubertal female rats behave and gain weight much like estradiol-deprived adults, not because of a lack of estrogenic stimulation, but because they are unresponsive to estradiol. This refractoriness to estradiol is probably due to pituitary growth hormone which may act on peripheral metabolic processes to alter the chemical feedback signals to the brain and interfere with neural restraint of eating behavior. It is interesting t o note that prolactin, which has many properties in common with growth hormone, may interfere with hypothalamic restraint of food intake during lactation and abolish responsiveness to estradiol, just as growth hormone

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does in weanling. Lactating females are hyperphagic, eating at least as much as nonlactating females with ven tromedial hypothalamic lesions. In addition, just as in weanling, ventromedial hypothalamic lesions do not induce additional hyperphagia or obesity in lactating females. Lesioned females do not become obese until lactation is terminated (Kennedy, 1953). This lactation-induced inhibition of ventromedial hypothalamic restraint of appetite also seems t o abolish responsiveness to exogenous estradiol. Treatment of lactating females with up to 5.0 pg estradiol benzoate/day does not significantly depress either food intake or body weight (Fleming, 1974 personal communication; J. M. Stern, 1974 personal communication). This refractoriness to estradiol benzoate is not due to high levels of plasma progesterone, since ovariectomized lactating rats do not respond to estradiol benzoate with a decrease in food intake or body weight (J. M. Stern, 1974 personal communication); it is likely that this refractoriness is partially due to prolactin. How could prolactin induce a refractoriness to estradiol in the neural feeding system? Prolactin probably does not act directly upon the brain to prevent the effects of estradiol benzoate. Treatment of ovariectomized virgin rats with prolactin has no effect on estrogenic suppression of food intake or body weight, indicating that the prolactin is probably not interfering with the estradiol activity directly (Fleming, 1974 personal communication). It is possible that the postparturient metabolic effects of prolactin (lactation) interfere with hypothalamic restraint of appetite and responsiveness t o estradiol, since a large amount of energy must be diverted into milk production. Ota and Yokoyama (1967a,b) have reported a hgh correlation between levels of lactation and food consumption in intact and ovariectomized postparturient rats; females with large litters eat more than females nursing small litters. This tremendous energy drain could induce the hyperphagia and mask hypothalamic restraint. Consistent with this possibility are data suggesting that estradiol benzoate treatments that interfere with prolactin secretion and lactation will also depress food intake (Fleming, 1974 personal communication; J. M. Stern, 1974 personal communication). Similarly, ventromedial hypothalamic lesions that interrupt lactation also induce an immediate obesity rather than a delayed obesity which can be produced by lesions that do not interrupt lactation (Kennedy, 1953). Thus, either growth hormone or prolactin appears to be able to act on metabolic processes of rats to mask hypothalamic restraint of food intake and, thereby, interfere with the appetite-depressing actions of estradiol. Note that there only seem to be certain times when growth hormone and prolactin have these effects. Immature rats are most responsive to growth hormone, whereas lactating females are highly responsive to prolactin. Adult cycling females are not especially responsive to either.


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VI. SEX DIFFERENCES IN NEUROENDOCRINE REGULATION OF BODY WEIGHT A.

ORGANIZING EFFECTS OF PERINATAL HORMONES

Males of most mammalian species are larger and heavier than their female conspecifics (Kakolewski et al., 1968; Tanner, 1962). This sex difference is also evident in rats; males eat and weigh more and exercise less than females in adulthood (see Section 11,A). What are the hormonal factors responsible for these striking differences in behavior and body weight? The most obvious explanation could simply be that, in adulthood, males and females secrete different hormones and that these different hormones are responsible for the sexual dimorphisms. Males secrete androgens that stimulate eating and weight gain but that are rather ineffective in stimulating exercise. On the other hand, females secrete large quantities of estrogens that depress eating and body weight and stimulate voluntary exercise (Section 111). Consistent with the possibility that the sexual dimorphism is determined by the activating effects of adult hormones is the report that the body weights of male and female rats differ only very slightly prior to 4-6 weeks of age, about the time the ovary begins to restrain body weight (Slob, 1972). Through 4 weeks of age the body weights of the two sexes are virtually identical; then the growth rate of the females slows and body weights diverge with age (Fig. 13). Thus, before the gonads are able to affect body weight (see Section V), there is almost no sex difference in body weight. However, although postpubertal gonadal secretions undoubtedly contribute to the sex differences in body weight, other factors must also be operating. Whereas adult gonadectomy may abolish the sex differences in carcass composition (males typically have a higher fat content) (Leshner and Collier, 1973), it does not abolish the sex difference in body weight (Kakolewski et al., 1968; Leshner and Collier, 1973). There is, of course, an obvious explanation for this inability to a b o h h the adult weight difference: by the time rats reach adulthood there are substantial differences in skeletal size that cannot be readily altered by gonadectomy. However, this is still only a partial explanation. Slob (1972) has shown that gonadectomy at 21 days of age, before there are any sex differences in body weight or skeletal size, attenuates, but does not abolish, the adult sex difference in body weight. Thus, a sexual dimorphism does develop in the absence of any postpubertal activating hormones, indicating that, although adult hormones do influence body weight, additional factors are also operating. What factors other than adult hormone secretions could be responsible for the sexual dimorphism in body weight? One factor could be genetic differences, since there is some sex difference in body weight at birth (King, 1915; Slob,

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1972). However, it is unlikely that genetic or prenatal factors play a significant role in determining the sex differences in body weight (see p. 246). Another possibility is that testicular hormones, secreted during the early postnatal period, are acting on the central nervous system and/or other nonneural tissues to alter 9 1

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the adult body weight set-point and adult responsiveness to activating hormones (Beatty et al., 1970; Bell and Zucker, 1971; Slob, 1972). An overwhelming body of evidence now suggests that many, if not all, sex differences in behavior and physiological functions are determined at least in part by the presence or absence of testicular androgens during a particular stage early in development. Since this field has been more than adequately reviewed (for a variety of viewpoints see, e.g., Beach, 1971; Gorski, 1971; Goy, 1970; Harris, 1964; Phoenix et al., 1967), I will attempt only a brief summary here. Early in development, the rat’s nervous system is inherently feminine, no matter what the animal’s genetic sex. In the absence of any androgenic stimulation the brain will continue to develop in a feminine pattern, will control cyclic pituitary gonadotropin secretion, and will show a typical feminine responsiveness to hormonal stimulation in adulthood. A feminine nervous system can be induced in genetically male rats by depriving them of perinatal androgens, usually by castration immediately after birth. On the other hand, if the developing rat’s brain is exposed to androgens sometime between the late prenatal period and approximately the tenth postnatal day, it will be masculinized and defeminized. In adulthood this masculine brain can only support tonic pituitary hormone secretion and is much less responsive to ovarian hormones than a nonmasculinized brain. Genetic female rats can be masculinized by a single injection of testosterone (or estradiol) shortly after birth. These permanent, irreversible effects of androgens early in development have been termed organizing effects, and stand in contrast to the transient, reversible activating effects of steroids secreted in adulthood (Phoenix et al., 1967). Therefore, it is quite possible that neonatal testicular secretions could also alter the neural substrates for body weight and regulatory behaviors, regardless of the hormones secreted in adulthood. Consistent with this possibility are the several reports that injection of female rats with testosterone propionate within the first week after birth increases body weight in adulthood when compared with vehicle-treated littermates (Beatty et al., 1970; Bell and Zucker, 1971; Slob, 1972; Swanson and van der Werff ten Bosch, 1963; Valenstein, 1968). However, these data by themselves do not necessarily demonstrate that neonatal testosterone organizes body weightregulating mechanisms. It is entirely possible that all these neonatal androgen injections are doing is to suppress ovarian functioning in adulthood; that is, perhaps the androgenized females weigh more simply because they are estrogendeprived as adults. To demonstrate conclusively that neonatal hormones do organize body weight-regulating mechanisms, it must be shown that neonatal hormonal manipulations affect adult body weight in the absence of activating hormones in adulthood. This has been done. Slob (1972) has found that whereas gonadectomy at 21 days of age (before the sexes diverge) does not prevent the adult sexual dimorphism in body weight, gonadectomy on the day of birth abolishes the adult sex difference in body

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weight (see Fig. 13). Thus, the gonads are doing something between birth and 21 days of age that results in a later divergence in body weight. Furthermore, it is the neonatal testis, and not the ovary, that is responsible for the sex difference. There is n o difference between day 1 and day 21 ovariectomized females in adult body weight, but males castrated on day 1 are significantly lighter than day 2 1 castrates in adulthood (Slob, 1972). An important point emerging from this work is that neonatal gonadectomy abolishes adult sex differences in body weight, indicating that neither genetic nor prenatal environmental factors are sufficient to cause the adult sexual dimorphism. If neonatal castration reduces male body weights, will neonatal testosterone injections increase female body weights in the absence of ovaries? Both Slob (1972) and Bell and Zucker (1971) have found that a single neonatal injection of testosterone propionate significantly increases the adult body weights of female rats ovariectomized just after birth. The results of these experiments demonstrate that neonatal androgens can organize adult body weight-regulating mechanisms independently of adult activating hormones. Of course, we have seen that adult hormones d o also play a role in determining the sex difference, so that gonadal hormones both organize and activate sex differences in body weight in rats. There may be a third way in which gonadal steroids contribute to sexual dimorphisms in body weight: by an interaction between organizing and activating influences (i.e ., neonatal hormones may organize adult responsiveness t o the activating hormones). It is very clear from the work on copulatory behavior that male and female rats are not equally responsive to activating hormones and that this sex difference is determined by neonatal hormones (see Beach, 1971, for a discussion of this point). Bell and Zucker (1971), Slob (1972), and Beatty et al. (1970) have examined the effects of neonatal hormonal manipulations (gonadectomy and/or various steroid treatments) on adult responsiveness t o steroids. There seems t o be a general consensus that neonatal exposure to testosterone enhances the weightpromoting effects of low doses of testosterone propionate given to gonadectomized adult rats of either genetic sex. Although it is clear that neonatal androgen treatment increases body weight in female rats, this treatment does not abolish responsiveness to ovarian hormones. Adult ovariectomy increases body weight in rats treated with testosterone neonatally, indicating that the ovary does restrain weight gain in these animals. However, Bell and Zucker (1971) have found that, whereas nearly all of their neonatal treatment groups lost weight during adult injections of a mixture of estradiol benzoate and progesterone, animals exposed t o testosterone just after birth lost significantly less weight than nonandrogenized rats. These experiments indicate that neonatal hormone exposure does organize adult responsiveness to the body weight effects of adult activating hormones; animals exposed to androgens in infancy are less responsive to the weight-depressing actions of ovarian hormones than are animals not androgenized as neonates.


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In summary, there are three ways in which gonadal steroids act to determine the sex differences in adult body weight in rats. First, neonatal testicular secretions organize body weight-controlling mechanisms to enhance adult body weight independently of adult steroidogenesis. Second, hormones secreted in adulthood act either to promote (testosterone) or to inhibit (estradiol) further weight gain, i.e., activating effects. Finally, there is an interaction between the organizing and activating effects. The neonatal hormonal environment determines the adult responsiveness to ovarian and testicular hormones. It is clear that neonatal hormones have organizing effects on adult body weight, but are the sex differences in behavior organized similarly? Neonatal androgen exposure decreases voluntary activity levels of rats and attenuates adult running responses to exogenous estradiol. Gerall (1967) reported that a single injection of 1250 pg testosterone propionate at 5 days of age significantly reduced adult running wheel activity when rats were tested with their ovaries. In addition, Gerall et al. (1972) have shown that neonatal injection of 5, 10, or 1250 pg testosterone propionate reduces running wheel activity in a dosedependent fashion, when rats are ovariectomized and injected with exogenous estradiol benzoate as adults. Harris (1964) has indicated that, when both groups are given ovarian transplants, neonatally castrated male rats show higher levels of running wheel activity than males castrated as adults. Therefore, i t appears that naonatal exposure to androgens greatly reduces adult running responses to either endogenous or exogenous estradiol. In contrast to the several published reports of organizing effects of steroids on body weight in rats, I am awaR of only one systematic study of the organizing and activating effects of sex hormones on eating behavior (Bell and Zucker, 197 1). From this work it appears as though the sex difference in eating behavior is little affected by the neonatal hormonal environment in the absence of activating hormones. Bell and Zucker found that, whereas intact males ate more than intact females, gonadectomized adults of both sexes displayed intermediate levels of food intake that were not affected by neonatal hormone manipulations (gonadectorny and/or androgen treatment). Animals exposed t o neonatal androgens weighed, but did not eat, more than nonandrogenized animals in the absence of activating hormones. The neonatal hormonal environment did not seem to have much effect on the eating responses of male rats when they were given exogenous hormones in adulthood. Testosterone propionate, which stimulated weight gain more in neonatally androgenized rats, did not differentially affect food intake in males, regardless of neonatal treatment. Also, the estradiol benzoate + progesterone, which depressed body weight more in the nonandrogenized groups, seemed to be equally effective in inhibiting food intake in all neonatal treatment groups in males. By contrast, the eating responses of female rats to activating hormones were dramatically affected by neonatal androgen injections. Females treated neonatally with oil decreased their food intake significantly more than neonatally

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androgenized females when treated with estradiol benzoate + progesterone as adults (Bell and Zucker, 1971). We have found that male rats castrated as adults and neonatally androgenized females show significantly smaller decreases in food intake than do nonandrogenized females when given estradiol benzoate alone as adults (Gentry and Wade, 1975). Why should the eating responses of females be affected by neonatal androgen treatments when those of males apparently are not? One possibility is that, in the Bell and Zucker experiment, all of their males had already been at least partially masculinized by endogenous testosterone prior t o any neonatal manipulations. According to their procedure, the rats were castrated “within the first 24 hr after birth.” However, as Thomas and Gerall(l969) point out, significant masculinization is occurring just hours after birth. These few hours of androgen exposure may have been sufficient to alter the adult eating respones of the males. Another possibility is that when Bell and Zucker were comparing the responsiveness of the various neonatal treatment groups to ovarian hormones, they injected a combination of estradiol benzoate and progesterone. It has been shown that if lordosis is used as a behavioral end point, neonatal androgenization reduces behavioral responsiveness to both estradiol and progesterone. In fact, the effect on responsiveness to progesterone may be the more dramatic of the two (Clemens et al., 1970). Therefore, the possibility remains that so far as eating behavior is concerned the male rats exposed to androgens neonatally might be less responsive to both the appetite-depressing action of estradiol and the appetite-stimulating action of progesterone. If both estradiol and progesterone are given simultaneously, the two effects might cancel one another, and it would appear as though the androgenized and nonandrogenized males are equally responsive t o ovarian steroids. This possibility remains to be tested. In conclusion, it is clear that the sex differences in adult rats’ body weights are due to both organizing and activating effects of gonadal hormones. The neonatal environment directly affects adult body weight-regulating mechanisms and also alters adult responsiveness to activating hormones. The activating hormones secreted in adulthood then act to exaggerate these sex differences. B. SEX DIFFERENCES IN HYPOTHALAMIC CONTROL OF BODY WEIGHT

Since the brain seems to defend different body weight set-points and compositions in male and female rats, reports that hypothalamic lesions produce different effects on eating and body weight in the two sexes should not be especially startling. Cox etal. (1969) found that lesions of the ventromedial hypothalamus caused greater hyperphagia and increase in weight gain in female rats than in males.


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Following ventromedial hypothalamic lesions, females showed a dramatic hyperphagia (around a 70% increase in eating) and increased weight gain, but males were only moderately hyperphagic (about a 20-30% increase) and showed n o weight gain when compared with unlesioned controls. These data have essentially been reproduced using a more palatable high-fat diet (Cox et al. used ground Purina rat chow) (Rehovsky and Wampler, 1972). Gold (1970) has also found that a combination of a high-fat diet and bilateral parasaggital knife cuts between the ventromedial and lateral hypothalamus resulted in greater overeating and weight gain than Cox et al. (1969) found with electrolytic lesions. However, the sex difference persisted; females showed a greater hyperphagia and weight gain relative to unoperated controls than the males did. Therefore, although there may be some differences in interpretation of the results (Gold, 1970; Rehovsky and Wampler, 1972), it is clear that either ventromedial hypothalamic lesions or parasaggital knife cuts produce a greater hyperphagia and weight gain in female than in male rats on a variety of diets when lesioned animals are compared to unlesioned controls (or to their own preoperative data). What is the physiological basis for this sex difference in response to ventromedial hypothalamic lesioning? In experiments in which comparisons are easily made (Cox et al., 1969; Gold, 1970), it is apparent that the sex differences in body weight gain are much more impressive in unlesioned rats than in lesioned rats. Before ventromedial hypothalamic lesions (or in sham-operated controls), males eat more and gain weight faster than females. After lesioning, males and females seem t o gain at nearly the same rate. In the Cox et ul. experiment, males showed no increase in weight gain after lesioning, but females increased their rate of weight gain to match that of the males. In the Gold experiment, the knife cuts accelerated the males’ weight gain, but the females increased weight even more so that they were gaining at approximately the same rate as the lesioned males. Therefore, i t appears as though there is n o sex difference in weight gain following ventromedial hypothalamic damage; the sexual dimorphism in response to lesioning is due to the abolition of the prelesioning sex difference in weight gain. If this is the case, perhaps we should rephrase the problem: Why is there a sex difference in prelesion body weight, and why does a ventromedial hypothalamic lesion abolish this difference? I hope that the first half of this question was answered, at least in part, in the previous section. Males seem to be heavier than females because of both organizing and activating actions of sex steroids (see Section V1,A). But why should ventromedial hypothalamic lesions abolish both the organizing and activating influences of sex hormones on body weight gain? Let us first consider the activating effects. Valenstein et al., (1969) suggested that ventromedial hypothalamic lesions may be partially gonadectomizing rats by decreasing pituitary gonadotropin release. In fact, they did find some

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evidence of gonadal atrophy (suggesting decreased hormone output) following their lesions. If this is the case, then a reduction in circulating estradiol should enhance weight gain, whereas a decrease in testicular androgen output should decrease weight gain. A partial gonadectomy could certainly contribute to the sex difference. Whether or not the lesions of the ventromedial hypothalamus decrease circulating hormone titers, these lesions could also interfere with the activating effects of steroids by removing some of their neural sites of action. Recall that estradiol implanted in the ventromedial hypothalamus depressed eating and body weight (Beatty etal., 1974; Porterfield and Stern, 1974; Wade and Zucker, 1970c) and that lesions of the ventromedial hypothalamus attenuated the weight-depressing actions of estradiol (Beatty er al., 1975; King and Cox, 1973). Thus, the lesions could be (partially) functionally ovariectomizing the females by removing a neural site of action of estradiol. Thus, there are at least two ways ventromedial hypothalamic lesions could interfere with the activating effects of sex hormones and contribute to the attenuation of the sex difference following lesioning: by causing gonadal atrophy and/or by removing some of the neural target sites for estradiol. If an attenuation of the activating effects is really a contributing factor, then longterm gonadectomized rats should show a significantly reduced sex difference in response to ventromedial hypothalamic lesions. Conadectomy substantially reduces the normal sex difference in body weight in adult rats. Reducing the prelesioning sex differences should also attenuate the relative changes following lesioning, since the similar postlesion weight gains would be compared with more comparable base-line values. Although some effort has been made in this direction (Valenstein er ul., 1969), the appropriate experiments remain to be done. Ventromedial hypothalamic lesions could also abolish the sex differences in hypothalamic regulation of body weight organized by neonatal hormone exposure. It has been shown that neonatal exposure to androgens permanently raises adult body weight independently of activating hormones (see Section VI,A), and Beatty et ul. (1970) have argued that testosterone might act on hypothalamic weight-regulating systems to produce this effect. It would not be unreasonable to suppose that the ventromedial hypothalamus might be a site of neonatal androgen action (Gorski, 197 1). Perhaps, then, ventromedial hypothalamic lesions dictate a high (and similar) level of body weight in both males and females. Consistent with this possibility is the report that neonatally androgenized females, whose prelesion body weights are intermediate between those of normal males and females, show a response to ventromedial hypothalamic lesions that is intermediate t o those of normal males and females (Valenstein, 1968). However, because these rats were tested with their gonads intact, it is not possible to rule out the possibility that the androgenized females were different from the normal females simply because their ovaries were secreting different activating hormones prior to lesioning.


25 1

To summarize, it has been suggested that male and female rats respond differently to ventromedial hypothalamic lesions, not because there is a sex difference in weight gain after lesioning, but because they start from different body weight set-points (levels of weight gain). Males are heavier (and gain faster) than females. Therefore, when similar postlesion weight gains are compared with different baselines, females exhibit a greater change. There are several ways in which ventromedial hypothalamic lesions could interfere with the organizing and activating effects of sex steroids that are responsible for the prelesion sex differences. Pfaff (1969) has very cleverly suggested another cause for the sex difference in hypothalamic hyperphagia and obesity-one that is independent of gonadal steroids. He noted that growth hormone injections stimulated weight gain in hypophysectomized male rats, but they were relatively ineffective in females. On the other hand, daily injections of prolactin stimulated eating and weight gain more in hypophysectomized females than in males. It has been known for some time that lesions of the medial basal hypothalamus decrease pituitary growth hormone secretion and also disinhibit pituitary secretion of prolactin (McCann et al., 1968). Thus, after ventromedial hypothalamic lesions, the drop in plasma growth hormone levels could inhibit weight gain in males without having much effect in females. On the other hand, the postlesioning increase in plasma prolactin should increase the eating and weight gain of females without affecting the males. Perhaps, then, these changes in pituitary hormone secretion are responsible for the sex differences (Pfaff, 1969). Although this hypothesis seems to be quite reasonable, I am not as yet convinced that this is really the basis for the sex difference in hypothalamic obesity. It has been exceptionally difficult, if not impossible, to influence the eating and weight gain with exogenous growth hormone or prolactin in nonhypophysectomized rats (Fleming, 1974 penonal communication; Gentry and Wade, 1974 unpublished data). In addition, i t appears as though hypophysectomized female rats gain weight nearly as fast as nonhypophysectomized females after ventromedial hypothalamic lesions (Valenstein et ul., 1969). Pfaffs hypothesis would predict a substantial difference between the two groups. Clearly, more research is necessary to evaluate this hypothesis. There also appears to be a sex difference in the effects of lateral hypothalamic lesions in rats. Powley and Keesey (1970) reported that male rats that had “recovered” from lateral hypothalamic lesions chronically regulated their body weight at a point below that of unlesioned control males. For this and other reasons, they suggested that lateral hypothalamic lesions permanently lower the body weight set-point, just as ventromedial hypothalamic lesions seem to raise the body weight set-point permanently (Hoebel and Teitelbaum, 1966). However, several laboratories have failed to observe this phenomenon in lesioned female rats; after lateral hypothalamic lesions, female rats regulate their body weight at levels identical to those of unoperated controls (Cox and

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Kakolewski, 1970; Harrell and Balagura, 1975; Mufson and Wampler, 1972). Why did Powley and Keesey (1970) find a chronically reduced body weight after lateral hypothalamic lesions in male rats whereas other researchers did not reproduce these findings in females? Mufson and Wampler (1972) rejected the possibility of a sex difference in response to lesions and instead suggested that the Powley-Keesey phenomenon was simply due to finickiness induced by the lesions. They suggested that “recovered” lateral hypothalamic-lesioned rats are extremely finicky, and, because Powley and Keesey maintained their rats on a relatively unappealing diet (Purina rat chow and tap water), their animals were underweight because of hypophagia and dehydration. To support their claim, Mufson and Wampler point out that both their rats, given a very palatable high-fat diet and sweetened water, and those of Cox and Kakolewski, given a very attractive (to rats), moist cat and dog food, showed no chronic weight reduction. However, it is very clear that the Mufson and Wampler hypothesis simply does not account for the data. Cox and Kakolewski (1970) indicated that males lesioned and maintained exactly like their females responded as in the Powley and Keesey experiment; their body weight was chronically lowered even on a very palatable diet. Also, HarreIl and Balagura (1975) have recently replicated the Cox and Kakolewski results in females (no lowered body weight after “recovety”) maintained on Purina rat chow and tap water, which is the same diet as that used by Powley and Keesey. Finally, Keesey and Boyle (1973) have found that lateral hypothalamic-lesioned males are no more responsive t o adulteration of their diets than are unlesioned males. It seems clear that there is a true sex difference in weight regulation after lateral hypothalamic lesions that is quite independent of diet. Another possible explanation for this sex difference is that, perhaps, males can afford to lose some weight after a lateral hypothalamic lesion but that females cannot; that is, perhaps we are seeing a basement effect in females but not in males. It is well known that male rats have a higher carcass fat content than females do (Leshner and Collier, 1973). Perhaps it is this extra fat that is permanently lost in males after lateral hypothalamic lesions. Females could already be regulating at a minimum weight and they might have no excess fat to shed following a lesion. If this is the case, adding some body fat to females by prior ovariectomy (Leshner and Collier, 1973) should give them something t o lose, and ovariectomized females should show a chronic weight reduction after lateral hypothalamic lesions, just as males do. However, Harrell and Balagura (1975) have recently shown that ovariectomized females behave just as intacts do following lateral hypothalamic lesions. There is no permanent change in body weight-they weigh just as much as unlesioned ovariectomized females. Thus, the inability of lean intact females to lose additional weight cannot explain the sex difference.


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The sex difference in weight regulation following lateral hypothalamic lesions might be a consequence of a sex difference in thermoregulation after lesioning. Wampler (1974) has suggested that the lowered body weights following lesioning in males might be very sensitive to environmental temperature; slightly lowering room temperature seems to restore body weights to prelesion values. Harrell and deCastro (1974 personal communication) have noted that male rats are hyperthermic (by approximately l0C) for at least 2 weeks following lesioning. This hyperthermia may cause a chronic undereating or at least prevent the hyperphagia necessary to restore prelesion body weights in male rats. On the other hand, female rats do not seem to be hyperthermic following the same kinds of lesions. Perhaps the absence of a hyperthermia permits the females to overeat following the postlesion weight loss and to retum their weights to prelesion levels. In conclusion, it is clear that there is a sex difference in body weight response to lateral hypothalamic lesions. After lesioning, male rats exhibit a permanently lowered body weight, whereas females do not. The lowered body weight in males is not an artifact of finickiness, since the sex differences have been reproduced using a variety of diets. Nor can the females' failure to lose weight permanently be due to a shortage of expendable fat, since obese ovariectomized females show no evidence of lowered body weight after lesioning. A final possibility is that the sex difference in weight regulation might be secondary to a sex difference in thermoregulation following lateral hypothalamic lesions. This hypothesis remains to be tested.

VII. HORMONAL EFFECTS ON TASTE PREFERENCES AND DIETARY SELF-SELECTION A.

HORMONES AND TASTE PREFERENCES FOR NONNUTRITIVE SOLUTIONS

By now it should be apparent that gonadal hormones affect how much rats eat. These same hormones also seem to modulate the taste preferences of rats and selection of dietary components. Thus, sex hormones could alter body weight and composition in rats by influencing both how much and what the animals eat. In 24-hour, two-bottle preference tests with distilled water, adult female rats exhibit greater preferences for sweet solutions than do adult males. This sex difference exists for both nutritive (glucose) and nonnutritive (saccharin) sweets (Valenstein etul., 1967b) and has been replicated in several strains of rats (Valenstein et ul., 1967a; Wade and Zucker, 1969a). Zucker (1969) has shown that this sex difference in saccharin preference is primarily due to the stimu-

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latory actions of ovarian hormones. Whereas castration of adult male rats produces only small increases in saccharin preference, postpubertal ovariectomy substantially diminishes the saccharin preferences of females. High saccharin preferences can be restored in ovariectomized females by daily injections of a combination of estradiol benzoate (0.5 pglday) and progesterone (0.5 mglday). Neither estradiol benzoate nor progesterone alone in a wide range of doses is effective in altering saccharin preferences (Zucker, 1969). The sexual dimorphism in adult saccharin preference is also determined in part by organizing actions of neonatal steroids. A single injection of testosterone propionate on the fifth day of life significantly reduces the saccharin preferences of female rats in adulthood (Wade and Zucker, 1969b). In addition, estradiol progesterone treatments, which enhance the saccharin preference of ovariectomized females, are completely ineffective in male rats castrated as adults (Zucker, 1969). Thus, the sex difference in saccharin preference in adult rats is

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jointly determined by the activating effects of ovarian hormones in adulthood and by the organizing actions of neonatal androgens. In addition to stimulating saccharin preferences in adult females, ovarian hormones seem t o enhance responsiveness to aversive quinine solutions. Rats ovariectomized postpubertally will drink significantly more o f a very bitter 0.0075% solution of quinine sulfate than intact females will. Treatment of progesterone mixture, ovariectomized females with the estradiol benzoate iwhich stimulates saccharin intake, also restores responsiveness to quinine. As with saccharin intake, neither estradiol benzoate nor progesterone alone had any effect on quinine aversion in ovariectomized rats (Wade and Zucker, 1970b). Ovarian hormones appear to enhance responsiveness to both palatable and aversive nonnutritive solutions, stimulating both saccharin preference and quinine aversion. The changes in hormone secretion during various reproductive states also influence responsiveness to tastes (see Table I). Pregnant and pseudopregnant rats exhibit very dramatic decreases in saccharin preference and quinine aversion-just as can be shown with ovariectomized females (Figs. 14 and 15) (Wade and Zucker, 1969a, 1970b). Also, there is no sex difference in saccharin preference prior to puberty; both males and females reject saccharin. At about the

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time the females reach puberty their saccharin preferences increase, and the sex difference appears (Fig. 16) (Wade and Zucker, 1969a). There is a remarkable correlation between the responsiveness of rats to tastes and levels of various energy balance-regulating behaviors (see Table I). The only exception to this relation appears to be that taste preferences do not fluctuate with the estrous cycle but the other behaviors do (Wade, 1968 unpublished data). With this one exception, it is clear that rats demonstrating high food intake and weight gain and low levels of voluntary exercise (males and ovariectomized, pregnant, pseudopregnant, lactating or prepubertal females) are also relatively unresponsive to nonnutritive tastes. This very high correlation among the various behavion suggests that they have a common endocrine basis. We have hypothesized that, if estradiol secretion (or the plasma estradiol-to-progesterone ratio) is within a sufficiently high rang,as during the estrous cycle, then saccharin preference and quinine aversion are enhanced. If estradiol availability is reduced (as a consequence of low secretory rate or of high plasma proges-

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257

terone levels), then responsiveness to tastes is reduced (Wade, 1972; Wade and Zucker, 1969a, 1970b). Thus, estradiol appears to be the principal ovarian hormone regulating nonnutritive taste preferences, and progesterone has secondary facilitatory and inhibitory effects. This hypothesis is certainly consistent with the changes in taste responsiveness during pregnancy and pseudopregnancy and following ovariectomy. In addition to decreased estradiol availability another factor may be operating in prepubertal females: an insensitivity to estradiol. Recall that estradiol does not affect eating or exercise in female rats until they reach a certain body weight (see Section V). A similar insensitivity to estradiol could be responsible, at least in part, for the diminished taste responsiveness in weanlings. Consistent with this possibility is the demonstration that induction of precocious puberty (and adult hormone secretion) in female rats does not induce a precocious elevation of saccharin preference (Wade and Zucker, 1969a). These data also indicate that attainment of puberty is not sufficient to enhance saccharin intake. Rather, the onset of a preference for saccharin solution appears to be more closely correlated with body weight than with puberty or chronological age in female rats (Wade, unpublished data). These results suggest that for taste preferences, as with eating and voluntary exercise, onset of responsiveness to ovarian hormones may be triggered by the attainment of a certain body weight or composition. Although these experiments point out that ovarian steroids do affect the taste preferences of rats, they tell us little or nothing about how the hormones might be effecting these changes. There are, of course, several possibilities. The high correlations between taste preferences and the other behaviors could indicate that the fluctuations in taste preferences are simply an artifact of changes in one of the other behaviors. For example, high saccharin preferences occur in rats with low food intake (intact, cycling females) but not in rats that eat a great deal (males and noncycling females). It has been shown that food deprivation increases the saccharin intake of rats (Valenstein, 1967; Wade and Zucker, 1969b), so that the intact, cycling females might be drinking more saccharin solution simply because they are eating less. However, it is possible to dissociate the changes in eating and taste preferences. For example, treatment of ovariectomized rats with estradiol benzoate alone depresses food intake without affecting taste preferences (Zucker, 1969). In addition, prevention of the usual postmating increase in food intake does not affect the decrease in saccharin preference during pregnancy (Wade and Zucker, 1969a). Finally, food intake, but not taste preferences, fluctuates with the estrous cycle. Therefore, the changes in eating and taste preferences for nonnutritive solutions cannot be causally related. Similar arguments would apply to the correlations between taste preferences and other hormone-related behaviors. A somewhat similar hypothesis has been advanced by Marks (1974) to account for the changes in “stimulus reactivity.” Marks argues that responsive-

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ness to tastes is determined by body weight, with a high body weight dictating a low responsiveness to tastes. The changes in taste preference following hormone treatments are viewed as being secondary to the changes in body weight. There does, indeed, seem to be a correlation between body weight and taste preferences, since rats with low responsiveness to tastes (males and pregnant, pseudopregnant, or ovariectomized females) do tend to be heavier than intact cycling females. However, Marks’s (1974) data often fail to demonstrate a close relation between body weight and responsiveness to tastes. In addition, treatment of ovariectomized females with estradiol benzoate has been shown to reduce body weight without affecting taste preferences (Wade and Zucker, 1970b; Zucker, 1969). Body weight and taste preferences cannot be directly related. A third possibility is that ovarian hormones could act on peripheral taste receptors to alter taste sensitivity. Although it is known that sex hormones can directly affect taste receptors (Hoshishima, 1967), this hypothesis remains to be tested. Perhaps the most appealing possibility is that ovarian hormones could act directly on the brain to alter the reinforcing properties of the various tastes. Many of the limbic and hypothalamic sites where lesions alter responsiveness to tastes also take up and retain estradiol and progesterone. Some notable examples include ventromedial hypothalamus, olfactory bulbs, septa1 area, and medial amygdala (Beatty and Schwartzbaum, 1967; Gesell and Fisher, 1968; Kemble and Schwartzbaum, 1969; Pfaff and Keiner, 1973; Teitelbaum, 1955; Wade and Feder, 1972a). Perhaps estradiol and progesterone act on one or more of these neural sites to alter taste preferences. This hypothesis could be tested by intracerebral hormone implant studies. To summarize, it is clear that sex steroids influence preferences and aversions of rats for nonnutritive taste factors. Ovarian hormones enhance the responsiveness to tastes of female rats, and during times of low estradiol availability (pregnancy, pseudopregnancy, following ovariectomy) saccharin preference and quinine aversion are reduced. The prepubertal depression in saccharin intake may be due to a weight-related lack of responsiveness to hormones. Although it is clear that the changes in taste preference are not secondary to fluctuations in body weight or other hormone-related behaviors, we do not know how or where ovarian steroids act to influence taste preferences. One appealing (and testable) hypothesis is that these hormones act on hypothalamic or limbic sites to alter the reinforcing properties of tastes. B.

SELECTION OF DIETARY PROTEIN

So what if sex hormones affect responsiveness to saccharin and quinine solutions? Real rats are not likely to be given a choice between saccharin or quinine and distilled water. What is the biological significance, if any, of these hormone-


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dependent sex differences and fluctuations in responsiveness to nonnutritive tastes? We (Wade, 1972; Wade and Zucker, 1969a) have suggested that these changes in taste preferences may represent a hedonic mechanism that influences self-selection of dietary components by rats during various reproductive states. It is well known that, if rats are placed in a cafeteria situation and allowed to self-select their diets, they are able to choose a diet that is compatible with normal growth and health. It has also been demonstrated that if selecting rats are subjected t o various environmental or endocrinological manipulations, they are able to make adaptive changes in their dietary self-selection patterns (e.g., Richter, 1956). More recently, Leshner and his colleagues have examined the dietary selection patterns of rats given a choice between a carbohydrate diet (0% protein) and a high-protein diet (45% protein) under conditions of varying nutritional requirements (Collier et al., 1969; Leshner, 1972; Leshner and Collier, 1973; Leshner e t a l . , 1971, 1972; Leshner and Walker, 1973). In these experiments they found that rats would vary their protein and carbohydrate intakes separately to meet different nutritional needs. For example, if male rats’ energy requirements are increased by allowing them access to running wheels or by placing them in a cold environment, they increase their carbohydrate intake without altering protein consumption (Collier et ul., 1969; Leshner et ul., 1971). This is certainly adaptive, since carbohydrates are a ready source of energy. Sex and reproductive status also affect protein-carbohydrate choice (see Table I). Adult male rats select a higher proportion of their diet as protein than do adult cycling females. This sex difference is primarily attributable to the suppressive actions of ovarian hormones on protein intake. Postpubertal ovariectomy increases the proportion of the diet selected as protein by females to levels equivalent to those of intact males, but castration of adult males seems to have no effect on protein-carbohydrate selection (Leshner and Collier, 1973). Prepubertal female rats select a greater proportion of their diet as protein than do adult cycling females. In addition, protein intake increases during pregnancy and pseudopregnancy, whereas carbohydrate intake remains unchanged (Leshner et al., 1972; Richter, 1956; Richter and Barelare, 1938). However, there is no fluctuation in dietary self-selection during the estrous cycle (Leshner and Collier, 1973). Once again, these differences in protein-carbohydrate selection seem to make sense. The animals that choose a higher proportion of protein in their diets (males and ovariectomized, pregnant, pseudopregnant, or prepubertal females) are all growing more rapidly than intact cycling females. The increased protein intake would be expected to facilitate the laying-down of new tissues in these rats. There is one aspect of the dietary self-selection work that does not seem to make sense at first. Most of the animals that show a higher dietary protein selection than intact cycling females (males and ovariectomized, pregnant, or pseudopregnant females) have higher carcass fat proportions than the cycling

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females (Galletti and Klopper, 1964; Hervey and Hervey, 1966; Leshner and Collier, 1973). Why should increased protein selection be correlated with high carcass fat content? A closer inspection of the data reveals that these rats increase their proportion of dietary protein by increasing protein intake without reducing carbohydrate intake. Thus, they are eating at least as much carbohydrate as cycling females (Leshner and Collier, 1973; Leshner et al., 1972). However, none of these groups is nearly as active as intact females (see Section 111). Perhaps these animals store the calories ingested as carbohydrate as fat rather than using them as an energy source for exercise as is done by more active females. In this way similar carbohydrate intakes could result in very different carcass fat levels, independent of dietary protein consumption. How is this selection of dietary protein determined? Note the virtually perfect inverse correlation between responsiveness to nonnutritive tastes and protein intake (see Table I). Animals that are highly responsive to tastes select significantly less protein in their diets than animals that are less responsive to saccharin and quinine. Also note that, during estrous cycles, neither protein intake nor taste preferences change, even though all of the other behaviors d o fluctuate. For example at proestrus, total food intake drops, but the proportion selected as protein does not change (Leshner and Collier, 1973). This extremely high correlation between taste responsiveness and protein selection suggests that the two might be causally related. Perhaps the hormonerelated taste preferences have evolved as a hedonic mechanism to regulate protein intake during the varying conditions of nutritional requirement that accompany changes in reproductive status. Proteins do not seem t o be highly preferred foods for rats. The increased finickiness of intact cycling females should suppress protein intake. During the postweaning period, pregnancy, or in males, the reduced finickiness should permit an increased intake of the nonpreferred protein that is required for growth.

VIII. HORMONES AND WEIGHT REGULATION IN NONRAT SPECIES Although gonadal regulation of body weight has been studied most extensively in rats, sex hormones affect regulatory behaviors and body weight in a wide variety of mammalian species, ranging from rodents to primates. A literature survey by Kakolewski et ul. (1968) and my own informal survey reveals that gonadectomy alters body weight regulation in at least guinea pig, rats, hamsters, mice, dogs, cats, cattle, sheep, goats, swine, rhesus monkeys, baboons, and human being. Most commonly gonadectomy increases weight gain in females but decreases it in males; however, there are interesting exceptions to this rule (see below). In the following, I shall not attempt an extensive cataloging of all the difference species in which sex hormones affect body weight and the manner


26 1

in which they do so. Rather, I hope to discuss a few of the more interesting examples of gonadal regulation of body weight at three different phylogenetic levels: rodents, ruminants, and primates. A.

OTHER RODENTS

It is very likely that gonadal control of body weight is similar to that of the rat in a variety of rodents. Castration of male mice and guinea pigs inhibits weight gain, whereas ovariectomy of females increases body weight (Slob et ul., 1973; Wright and Turner, 1973), suggesting that in mice and guinea pigs, as in rats, estradiol inhibits and androgens promote weight gain. Adult male mice and guinea pigs are heavier than their female counterparts. As in rats, treatment of female guinea pigs with testosterone propionate early in development increases body weight and reduces the adult sex difference, so that the gonads may both organize and activate the sex differences in body weight (Slob etul., 1973). Finally, damage to the ventromedial hypothalamus in mice by gold thioglucose induces greater increases in body weight among females than males (Sanders et al., 1973; Wright and Turner, 1973). However, there is a very interesting exception to this ratlike control of body weight among the various rodents: the golden hamster. Adult female hamsters weigh and eat more than adult males (Kowalewski, 1969; Swanson, 1967; Zucker etul., 1972). Ovariectomy of adult or weanling female hamsters has no significant effect on body weight, but castration of males increases body weight until they become not significantly different from females. Treatment of gonadectomized adults with estrone or estradiol benzoate has no effect on either eating or body weight in males and females (Kowalewski, 1969; Swanson, 1968; Zucker et ul., 1972). It could be argued that insufficient estradiol benzoate was used in these experiments, since hamsters are much less responsive to estradiol than other rodent species (Feder et al., 1974b)-probably because of reduced neural affinity for the steroid. However, not even 10 pg estradiol benzoatelday, more than enough to induce sexual receptivity, had any effect on eating and body weight (Feder etul., 1974b; Zucker etul., 1972). On the other hand, treatment of adult gonadectomized male hamsters with testosterone propionate depresses both food intake and body weight, but it is ineffective in females (Zucker et uf., 1972). In addition, it has been reported that treatment of hamsters with high doses of progesterone (5 mg/day) increases both food intake and body weight. Progesterone seems to be more effective in females than in males (Swanson, 1968; Zucker et ul., 1972). However, for several reasons, it is very likely that this effect of progesterone is largely a pharmacological artifact and is of little significance to the intact hamster. First, progesterone doses less than 5 mg/day (a huge dose for a hamster) are not effective in altering eating and body weight. Second, and most important, changes in progesterone secretion during estrous cycles and

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pregnancy are typically not accompanied by fluctuations in food intake (Lukaszewska and Greenwald, 1970;Zucker et al., 1972). It appears, therefore, that androgens, rather than ovarian steroids are the important activating hormones in hamsters, so far as eating and body weight are concerned. Gonadectomy increases the body weight of males but leaves females unaffected. Testosterone treatment reduces the body weights of males but not of females; treatments with physiological doses of ovarian hormones are without effect in either sex. It seem as though testosterone has much the same effect in hamsters as estradiol does in rats. It would be interesting t o see whether testosterone-treated hamsters undereat and lose weight only until they reach a new body weight set-point, as do estradiol-treated rats. It is very likely that gonadal hormones organize as well as activate the sex difference in adult body weight. Exposure of female hamsters to testosterone during the first 10 days of life significantly reduces adult body weight (Gottlieb et al., 1974). In contrast to the very dramatic rat-hamster species differences in hormonal regulation of eating and body weight, the two species may be very similar with regard to gonadal effects on activity and taste preferences. If female hamsters are given access t o running wheels, their voluntary exercise fluctuates with the estrous cycle just as it does in rats. Activity is highest when the females are in heat. In addition, running wheel activity is substantially reduced during pregnancy and pseudopregnancy (Richards, 1966), just as in rats. These similarities suggest that the ovarian hormones might have identical effects on voluntary exercise in rats and hamsters. Hamsters also exhibit sex differences in saccharin preferences similar to those of rats. Females consume more saccharin than males. As in rats, the sex difference seems to be due to the stimulatory effects or ovarian hormones on saccharin preference. Ovariectomy of adult females significantly reduces saccharin preference, but castration of adult males has no substantial effect (Zucker et ul., 1972). These data from rodent species other than rats indicate that, although hormonal effects on body weight and regulatory behaviors may be widespread, generalizations from one species to another should be undertaken only with caution. B.

RUMINANTS

A great deal of research has been done on the effects of sex steroids on body weight and carcass quality in domestic ruminants, since factors affecting meat production and quality have widespread economic implications. Much of this work has been extensively and admirably reviewed (Baile and Forbes, 1974;Hafs et al., 1971). Until recently, diethylstilbestrol, a very potent nonsteroidal estrogen, was


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widely used by growers of cattle and sheep to improve meat production. In ruminants, treatment with diethylstilbestrol increases growth and improves meat quality. Although little is really known about how diethylstilbestrol exerts these effects, it has been suggested that the increased growth is due to a stimulation of pituitary growth hormone release. Both diethylstilbestrol and growth hormone have been reported to stimulate eating and weight gain, and there is some evidence indicating that diethylstilbestrol treatment increases pituitary and plasma growth hormone levels (see Baile and Forbes, 1974; Hafs et al., 1971, for more extensive discussions of this point and for documentation). Changes in endogenous hormone secretion appear to affect food intake in cows and ewes. Food intake of ewes drops at estrus, and the increased estrogen secretion during late pregnancy is also accompanied by a decrease in food intake in cows and ewes (Forbes, 1971; Tarttelin, 1968). These data might mean that endogenous estradiol may inhibit eating in sheep and cattle. Consistent with this possibility are the reports that exogenous estradiol treatments depress food intake in cows (Muir er al., 1972), ewes (Tarttelin, cited in Forbes, 1974), and wethers (Forbes, 1972). In addition, the appetite-depressing action of estradiol in cows can be reversed by progesterone (Muir el al., 1972). The recent work by Forbes (1974) indicates that ovarian steroids could affect eating in ruminants by a direct action on the brain. Injection of estradiol benzoate into the lateral cerebral ventricles of wethers increased food intake at low doses (10-20 pg) but decreased eating at higher doses. Concurrent intraventricular injection of progesterone attenuated the appetite-stimulating effects of low doses of estradiol benzoate (Forbes, 1974). Thus, i t is clear that gonadal steroids have significant effects on eating and body weight in ruminants. However, these actions of hormones may be very different, depending on the species, dosage, and form of the hormone given. C.

PRIMATES

Finally, although the order has not been studied to any great extent, i t appears as though gonadal steroids affect body weight and regulatory behaviors in a variety of primate species, including human being. There have been several reports indicating that food intake fluctuates with the menstrual cycle in rhesus monkeys and baboons (Gilbert and Gillman, 1956; Krohn and Zuckerman, 1938). John Czaja (cited in Goy and Resko, 1972) found that there was an abrupt drop in the percentage of the rhesus monkeys that ate their full daily ration of food midway between menstrual periods. This is the time when endogenous estradiol levels are rising rapidly or are at a maximum. Czaja also found that a single injection of estradiol benzoate (60 pg) produced a marked and significant decrease in food intake of ovariectomized rhesus monkeys within 24 hours. Injections of progesterone alone were ineffective in altering the food intake of ovariectomized rhesus females. Thus, ovarian hormones may affect eating behavior in nonhuman primates much as they do in rats.

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In human beings there are obvious sex differences in food intake and body weight, but the role of gonadal steroids in determining these sex differences is unspecified, as yet. It is clear that body temperature and, perhaps, body thermostatic set-point (Cunningham and Cabanac, 1971) fluctuate with the menstrual cycle. These body temperature fluctuations have been attributed t o “thermogenic” actions of endogenous progesterone during the luteal phase of the cycle (see Section 11,A). Gonadal hormones might also be of some consequence for the regulation of human alimentary preferences. Pangborn (1959) has noted that women have lower identification thresholds for sweet substances and in general are more sensitive to tastes than men are. Taste preferences also fluctuate with the menstrual cycle and pregnancy (Seifrit, 1961; Smith and Sauder, 1969; Suvorova, 1950; Thorn et ul., 1938; Wright and Crow, 1973). Wright and Crow (1973) have reported fluctuations in women’s pleasantness ratings for sucrose solutions with the menstrual cycle. Following a glucose meal, the sugar solutions were rated as being less pleasant, but this shift did not occur as rapidly around the time of ovulation. Smith and Sauder (1969) have also reported changes in food cravings during menstrual cycles. Cravings for certain foods, especially sweets, increased in the premenstrual period. Of course, there is n o shortage of anecdotal reports of unusual food preferences during pregnancy (RWade, 1971 and 1974 personal communications). It is not at all obvious that these fluctuations in taste preferences are due to hormones rather than to social and environmental influences on attitudes re. lating to sex and reproductive condition. These social-environmental influences are extremely important for the differentiation of gender identity and for the development of attitudes toward reproductive behaviors and physiology (e.g., Money and Ehrhardt, 1973). However, Nisbett and Gurwitz (1970) have reported that newborn baby girls are more responsive to sweetness and are less willing to work for their formula than baby boys are. These data suggest that sex and/or hormones may influence human alimentary behavior independent of any learned influences.

IX. CONCLUSIONS AND DIRECTIONS FOR FUTURE RESEARCH Gonadal hormones have dramatic and far-ranging effects on the behavioral regulation of energy balance in a wide variety of species. Over the past 50 years a great deal of descriptive research and simple endocrinological approaches have given us a good idea of how regulatory behaviors and body weight fluctuate with variations in reproductive status and which of the hormones are responsible for these fluctuations. But our work has really just begun. For example, we have almost n o knowledge of what the hormones are doing to the brain to effect


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these changes in body weight regulation. Clearly, a great deal of work remains to be done before we can begin to understand these hormone-behavior interactions. In female rats, estradiol is the principal ovarian steroid influencing behavioral regulation of energy balance. It is likely that estradiol acts directly on the brain to lower the set-point of a neural lipostatic mechanism. Lowering the body weight set-point reduces food intake which, in tum, lowers body weight (or the proportion of the total body mass devoted to fat stores). The changes in eating behavior following hormonal manipulations are seen as attempts to align body weight with the new set-point. A very likely site of action of estradiol on eating and body weight is the ventromedial hypothalamus, and estradiol may simply cause a “fme tuning” of the lipostatic control mechanisms in this part of the brain. This, of course, does not exclude the possibility of other neural sites of action. In contrast to the estrogenic effects on eating, estrogenic stimulation of voluntary exercise does not seem to be secondary to changes in body weight set-point . Progesterone also affects weight regulation in female rats. However, the principal effect of progesterone seems to be to attenuate or block the body weightregulating actions of estradiol. It is difficult to demonstrate effects of progesterone in the absence of estradiol. An exciting implication of this set-point hypothesis is that if this phenomenon is not restricted to rats (not an unreasonable assumption; see Section VIII), an estrogen-like compound could be used to lower body weight and combat obesity in human being. This approach would be feasible only if the neural estradiolsensitive system for weight regulation could be manipulated without affecting the other estradiol-sensitive systems in the body. Recent work with antiestrogens suggests that this may be possible. Perhaps an ideal weight-control drug would be one that acts on neural weight-regulating systems to lower body weight set-point without being estrogenic or antiestrogenic in other hormone-sensitive systems. Although a lipostatic hypothesis is an attractive and convenient way to describe the effects of estradiol and progesterone on eating and body weight, it is only a description and tells us little about what the steroids axe doing to neural tissues to change their functioning. We actually know very little about the biochemical mechanism of action of estradiol in neural tissues. Two principal approaches have been taken to study this problem. One has been to examine the uptake, binding, and genomic effects of estradiol in an attempt to compare the neural mechanism of action with that in peripheral tissues. Another approach has been to study interactions between sex hormones and brain neurotransmitters. This latter approach is plagued with numerous difficulties (see Section IV,C), but, in my opinion, it has a tremendous potential for creative, intelligent research. I hope that a great deal of progress can be made in studying hormone-neurotransmitter-eating behavior interactions in the near future.

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In addition to this ignorance of the biochemical effects of steroids on brain cells, there are other problems in the area of hormone action on the brain. For example, even though it has been demonstrated that hormones implanted in specific brain regions can affect eating or exercise, little is known about the neuroanatomical distribution of the hormone “receptors” for each behavior, or about the neural pathways activated once the estradiol reaches the brain4 Similarly, progesterone attenuates behavioral responsiveness to estradiol, but little is known about how or where it acts. Does progesterone act on the brain to inhibit estradiol responsiveness? Does it act on the same neurons that estradiol does? No clear answer has emerged as yet. Food intake, voluntary exercise, thermoregulatory behavior, taste preferences, and sexual receptivity all show highly correlated fluctuations during various reproductive states (see Table I). These data may mean that there are common endocrine factors underlying these changes, but they definitely do not mean that the various behaviors bear a cause-and-effect relation. It is very simple to dissociate these behaviors by hormonal manipulations. For example, estradiol implants in the ventromedial hypothalamus can depress food intake without affecting exercise or sexual receptivity, whereas placements in the anterior hypothalamus-preoptic area stimulate running wheel activity without affecting eating or lordosis. These behaviors can fluctuate independently, and competing behavior models cannot account for the coordinated pattern of behavioral changes. There are sex differences in body weight regulation in many species. In rats this sex difference is attributable to both activating effects of hormones secreted postpubertally and organizing effects of perinatal androgens. In adults the ovary secretes hormones that reduce body weight, whereas testicular androgens increase body weight. The presence or absence of androgens perinatally also influences adult body weight independent of any activating influences. Animals exposed to androgens neonatally are heavier as adults than nonandrogenized rats. Furthermore, exposure to neonatal androgens can also alter the responsiveness of the adult weight-regulating system to activating hormones. In spite of a great volume of research on the problem, there is no obvious consensus as to how neonatal androgens exert their effects on the nervous system. Sex hormones have some rather striking effects on preferences of rats for both rewarding and aversive nonnutritive tastes. It has been suggested that these 40ne interesting and testable possibility is that estradiol might affect eating and body weight by indirectly altering pancreatic insulin secretion. It is well known that the brain, particularly the ventromedial hypothalamus, can control insulin secretion (Woods and Porte, 1974). More recently evidence has begun t o accumulate suggesting that a hypersecretion of insulin is the cause of the overeating and obesity that follow ventromedial hypothalamic lesions (for reviews, see Bray, 1974; Woods et ul., 1974). Perhaps, then, estradiol acts via the ventromedial hypothalamus to depress insulin secretion and, thus, eating and body weight. If this is, in fact, the case, then ovarian hormones should not affect eating and body weight in diabetic rats maintained with controlled amounts of exogenous insulin.


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hormone-related taste preferences may represent a hedonic mechanism that has evolved to regulate the protein intake of rats during varying conditions of nutritive need. There is a nearly perfect inverse correlation between responsiveness to tastes and selection of dietary protein. However, virtually nothing is known about how sex hormones might alter dietary self-selection. We d o not know whether or not hormones even act on the brain to alter taste preferences. Although the adaptive advantage of altering protein intake t o meet needs imposed by reproductive status seems obvious, why total food intake and voluntary exercise of rats should be linked to gonadal steroid secretion is not so obvious. Is there any adaptive advantage to having voluntary exercise and body weight regulation tied to blood sex hormone levels? Although these questions cannot be answered with any certainty, it is easy to speculate. For example, an increase in locomotor activity at proestrus could increase a female’s chances of encountering a male and becoming impregnated. Also, it is obvious that an active mobile female rat is more attractive to males than an inactive female, which also increases the likelihood of her becoming pregnant. A lowered level of activity before puberty or during pregnancy would make more calories available for growth or for increasing the body’s energy stores prior to lactation and would decrease chances of predation. It is more difficult to understand why food intake should fluctuate with estrous cycles. Perhaps food intakeis linked to sex hormone secretion just to ensure that eating and energy stores will increase during pregnancy, and the fluctuations during estrous cycles are simply a by-product of this association. Acknowledgments Preparation of this paper was supported in part by National Institutes of Health grant NS-10873. My research that is cited in this paper has been supported at various times by grants HD-02982 (to Irvmg Zucker), HD-04467 (to Harvey Feder), and NS-10873 from the National Institutes of Health. Drs. William Beatty, Alison Fleming, Lindy Harrell, J. Bradley Powers, and Judith Stern have generously allowed me to cite their unpublished data. I am very grateful to Alison Fleming, Tom Gentry, Babs Marrone, Larry Morin, Ed Roy, and Irv Zucker for their many helpful and constructive criticisms of the earlier draft of this paper. Finally, I am much indebted to Nancy Zygmont for her cheerful assistance. References Ahlskog, J. E., and Hoebel, B. G. 1973. Overeating and obesity from damage t o a noradrenergic system in the brain. Science 182, 166-169. Ahlskog, J. E., Hoebel, B. G., and Breisch, S. T. 1974. Hyperphagia following lesions of the hypothalamic noradrenergic pathway is prevented by hypophysectomy. Fed. Proc., Fed. Amer. Soc. Exp. Biol. 33,463. Anderson, C. H., and Greenwald, G. S. 1969. Autoradiographic analysis of estradiol uptake in the brain and pituitary of the female rat. Endocrinology 85, 1160-1 165. Anton-Tay,F., and Wurtman, R. J. 1968. Norepinephrine: Turnover in rat brains after gonadectomy. Science 159 1245.

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Drewett, R. F. 1974. The meal patterns of the oestrous cycle and their motivational significance. Quart. J. Exp. Psychol. 26,489-494. Emerson, J.D. 1955. Development of resistance to growth promoting action of anterior pituitary growth hormone. Amer. J. Physiol. 181, 390-394. Epstein, A. N., and Teitelbaum, P. 1967. Specific loss of hypoglycemic control of feeding in recovered lateral rats. Amer. J. Physiol. 213, 1159-1 167. Feder, H. H., Resko, J. A , and Goy, R. W. 1968. Progesterone levels in the arterial plasma of pre-ovulatory and ovariectomized rats. J. Endocrinol. 41,563-569. Feder, H. H., Naftolin, F., and Ryan, K. J. 1974a. Male and female sexual responses in male

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function. I n “Frontiers in Neuroendocrinology, 1971” (L. Martini and W.F. Ganong, eds.), pp. 237-290 Oxford Univ. Press, London and New York. Gottlieb, H., Gerall, A. A., and Thiel, A. 1974. Receptivity in female hamsters following neonatal testosterone, testosterone propionate, and MER-25. Physiol. Behuv. 12, 61-68. Goy, R. W. 1970. Experimental control of psychosexuality. Phil. Trans. Roy. Soc. London, Ser. B 259, 149-162. Goy, R. W.,and Resko, 1. A. 1972. Gonadal hormones and behavior of normal and pseudohermaphrodite nonhuman female primates. Recenf Progr. Horm. Res. 28,707-733. Greene, J . , Wells, J., and Ivy, A. 1939. Progesterone will maintain adrenalectomized rats. Proc. SOC.Exp. Biol. Med. 40,83-86. Grossman, S . P. 1968. Hypothalamic and limbic influences on food intake. Fed. Proc., Fed. Amer. SOC.Exp. Biol. 27, 1349-1360. Grunt, J. A. 1964. Effects of adrenalectomy and gonadectomy on growth and development in the rat. Endocrinology 75,446-451. Hafs, H. D., Purchas, R. W., and Pearson, A. M. 1971. A review: Relationships of some hormones to growth and carcass quality of ruminants. J. Anim. Sci. 3 3 , 6 4 7 1 . Hainsworth, F. R. 1967. Saliva spreading, activity, and body temperature regulation in the rat. Amer. J. Physiol. 212, 1288-1292. Hamilton, C. L., and Brobeck, J. R. 1964. Food intake and temperature regulation in rats with rostra1 hypothalamic lesions. Amer. J. Physiol. 207,291-297. Han, P. W. 1967. Hypothalamic obesity in rats without hyperphagia. Trans. N. Y.Acud. Sci. 30,229-243. Harrell, L. E., and Balagura, S. 1975. The influence of ovarian hormones on the recovery period following lateral hypothalamic lesions. J. Comp. Physiol. Psychol. 88, 194201. Harris, G. W. 1964. Sex hormones, brain development and brain function. Endocrinology 75,627-648. Hashimoto, I., Henricks, D. M., Anderson, L. L., and Melampy, R. M. 1968. Progesterone and pregn-4en-20&01-3-one in the ovarian venous blood during various reproductive states in the rat. Endocrinology 82, 333-341. Hervey, E., and Hervey, G. R. 1966. The relationship between the effects of ovariectomy and of progesterone treatment on body weight and composition in the female rat. J. Physiol. (London) 87,44P45P. Hervey, E., and Hervey, G. R. 1967. The effects of progesterone on body weight and composition in the rat. J. Endocrinol. 37, 361-384. Hervey, E., Hervey, G. R, and Berry, P. M. 1967. A comparison between the changes in body weight and composition in female rats during pregnancy and during progesterone treatment. J. Endocrinol. 38, iii-iv. Hervey, G. R. 1969. Regulation of energy balance. Nufure (London) 222,629-631. Hervey, G. R., and Hervey, E. 1965. Interaction of the effects of oestradiol and progesterone on body weight in the rat. J. Endocrinol. 33, ix-x. Hervey, G. R, and Hutchinson, I. 1973. The effects of testosterone on body weight and composition in the rat. J. Endocrinol. 57, xxiv. Hitchcock, F. A. 1925. Studies in vigor V. The comparative activity of male and female albino rats. Amer. J. PhysioL 75,205-210. Hoebel, B. G. 1971. Feeding: Neural control of intake. Annu. Rev. Phvsiol. 33. 5 33-568.

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Subject Index estradiol and progesterone in interaction with brain monoaminergic systems, 234-236 mechanism of action of, 225-234 site of action of, 215-225 hormonal effects on food selection and, 25 3-260 hypothalamic, 248-253 lactation and, 237-242 organizing effects of perinatal hormones in, 243-248 in primates, 263-264 reproductive condition and, 204-206 responsiveness to ovarian steroids and, 237-242 in rodents, 261-262 in ruminants, 262-263 sex differences in, 203-204 Brain estradiol and progesterone in body weight regulation and, 215-236 mechanisms of sexual behavior in, 159-200 biochemical factors in androgen action, 165-173 hypothalamic androgen concentration, 185-190 hypothalamic sensitivity to androgen, 173-1 85 localized steroid effects in, 1 6 6 1 6 5

A Adoption aunting and, 128-1 30 by male, 107-108 Agonistic buffering, by male, 108-1 10 Androgen action of environmrntal factors and, 182-185 metabolism and, 170-172 specificity and, 173 uptake and, 165-170 prolonged deficit of, 174-180 sensitizing effects of, 180-182 structure of courtship and, 185-190 Attraction, infant care and, 142-145 Aunting, 120-142 adoption and, 128-130 benefits for mother-infant pair, 130-133 incompetence, kidnapping, and aunting to death, 125-128 infant independence and, 133-1 36 learning to mother and, 122-125 preferred and available aunts and infants, 137-142 status benefits and, 136-137 Aversions to poison, in rats, 34-38 specific hungers and, 42-43 taste and, 49-50 Avoidance of predators, social transmission of, 87-88

C Calorie hunger, in rats, 33-34 Caretaking, see Infants Chicken, food selection in, 51-52 Conditioning, in social transmission, 88-92 Conspecific caretaking, see Infants Copulatory behavior, steroid effects in brain and, 161-163 Courtship, hypothalamic concentration of androgen and, 185-190 Culture, food selection and, 62-67

B Baby-sitting, by male, 106-107 Behavior, see also specific behaviors developmental determinants of classification in terms of, 8-12 inirial, 2-8 relevant experience, 12-1 7 Behavioral transmission, see Social transmission Behavioral units, 4 4 Birds, social transmission of vocalizations in, 88 Body weight regulation, 201-279 activating effects of sex hormones in females, 210-215 in males, 207-210

D Developmental determinants behavior classification in terms of, 8-12 initial, 2-8 relevant experience, 12-17 281

282

SUBJECT INDEX

Domestication, food selection and, 50-51

E Environment, infant care and, 145-148 Estradiol interaction with brain monoaminergic systems, 234-236 mechanism of action of, 225-234 site of action of, 215-225 Ethnicity, food selection and, 5 8 4 2 Experience, relevant, 12-17 Exploitation of infant, by male, 104-1 18

F Feeding behavior, social transmission of, 84-87 Food selection, 21-76 in chickens, 51-52 in generalists, 27 hormonal effects on, 253-258 in humans, 52-53 biological factors in, 53-56 culture and, 62-67 ethnic-racial differences in, 58-62 specific hungers and, 56-57 in rats, 27-29 calorie hunger and, 33-34 domestication and, 50-51 poison avoidance and, 34-38 sodium hunger and, 30-33 specific hungers and, 38-49 tasteaversion learning and, 49-50 water hunger and, 29 in specialists, 24-27

selection of dietary protein and, 258-260 taste preferences and, 253-258 Humans, food selection in, 52-53 biological factors in, 53-56 culture and, 62-67 ethnic-racial differences in, 58-62 specific hungers and, 56-57 Hunger (s) for calories, 33-34 for sodium, 30-33 specific in humans, 56-57 in rats, 38-49 for water, 29 Hypothalamus androgen concentration in, 185-1 90 body weight regulation and, 248-253 sensitivity to androgen, 173-1 85 I

Incompetence, aunting and, 125-1 28 Infanticide aunting and, 125-128 by male, 110-1 1 3 Infants, conspecific caretaking of, 101-158 aunting, 120-142 male care vs. exploitation, 104-1 18 nurture vs. abuse, 118-120 selective pressures on infant, 142-148 K Kidnapping, aunting and, 125-1 28

L G

Generalists, food selection by, 27 rats, 27-51 Gonadectomy, body weight regulation and in females, 210-215 in males, 207-210

H Hormones, see also Steroids; specific

hormones in body weight regulation activating effects of, 207-215 in nonrat species, 260-264 organizing effects of, 243-248

Lactation, body weight regulation and, 237-242 Lactose intolerance, 59-62 Learning of maternal behavior, 122-125 social, 88-92

M Male-infant interactions, 104-1 18 adoption, 107-108 agonistic buffering, 108-1 10 baby-sitting, 106-107 degree of relationship in, 113-118 infanticide, 110-1 13

SUBJECT INDEX protection and rescue, 105-106 Maternal behavior, learning of, 122-125 Metabolism, of androgen, 170-172 N

Natal coats, infant care and, 142-145 Novelty, specific hungers and, 4 1 4 2

0 Omnivores, food selection in, 27 P Phenylthiocarbamide, ability to taste, 58-59 Phylogeny, infant care and, 145-148 Poison avoidance, in rats, 34-38 Precopulatory behavior, steroid effects in brain and, 163-165 Predator avoidance, social transmission of, 87-88 Predatory behavior, social transmission of, 84-87 Preferences specific hungers and, 4 2 4 3 taste, hormonal effects on, 253-258 Primates, body weight regulation in, 263-264 infant care in, 101-158 aunting and, 120-142 male care vs. exploitation, 104-118 nurture vs. abuse, 118-120 selective pressures on infant and, 142-148 Progesterone interaction with brain monoaminergic systems, 234-236 mechanism of action of, 225-234 site of action of, 215-225 Protection, by male, 105-106 Protein, hormonal effects on selection of, 258-260

R Race, food selection and, 58-62 Rats

283

body weight regulation in, see Body weight regulation food selection by, 27-29 calorie hunger and, 33-34 domestication and, 50-5 1 poison avoidance and, 34-38 sodium hunger and, 30-33 specific hungers and, 3 8 4 9 bte-aversion learning and, 49-50 water hunger and, 29 Reproductive condition, body weight regulation and, 204-206 Reproductive success, learning to mother and, 125 Rescue, by male, 105-106 Rodents, see also Rats body weight regulation in, 261-262 Ruminants, body weight regulation in, 262-263

s Sex differences, in body weight regulation, 203-204 neuroendocrine, 243-25 3 Sex hormones, see also specific hormones

activating effects in body weight regulation, 207-215 Sexual behavior, 159-200 biochemical factors in androgen action and, 165-173 hypothalamic androgen concentration and, 185-190 hypothalamic sensitivity to androgen and, 173-185 localized steroid effects in brain and, 160-165 Social transmission, 77-100 of bud vocalizations, 88 of feeding and predatory behavior, 84-87 learning and conditioning paradigms for, 88-92 of predator avoidance, 87-88 of spatial utilization, 82-84 terminology for, 92-95 Sodium hunger, in rats, 30-33 Spatial utilization, social transmission of, 82-84 Specialists, food selection in, 24-27

284

SUBJECT INDEX

Specific hungers in humans, 56-57 in rats, 38-49 Specificity, see also Developmental determinants of androgen, 173 Steroids, see also Hormones;specific hormones in body weight regulation, 237-242 copulatory behavior and, 161-163 precopulatory behavior and, 163-165

T Taste hormonal effects on preferences for, 253-258 of phenylthiocarbamide, 58-59 Thiamine-specific hunger, in rats, 38-41, 46 W

Water hunger, in rats, 2 9

A 6 E l

c a 0 9

E O F C H 1 J

1 2 3 4 5

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