Handbook of Psychopharmacology

Volume 7 Principles of Behavioral Handbook of Psychopharmacology

SECTION I: BASIC Volume 1 Biochemical Principles and Techniques in Neuropharmacology Volume 2 Principles of Research Volume 3 of Biogenic Amines Volume 4 Amino Acid Volume 5 Synaptic Modulators Volume 6 Biogenic Amine Receptors

SECTION II: BEHAVIORAL PHARMACOLOGY IN ANIMALS Volume 7 Principles of Behavioral Pharmacology Volume 8 , Neurotransmitters, and Volume 9 Chemical Pathways in the Brain

SECTION III: HUMAN PSYCHOPHARMACOLOGY Volume 10 N euro leptics and Volume 11 Volume 12 Drugs of Abuse Volume 13 Biology of Effects in Affective Disorders Volume 14 Anxiety and Affective Disorders: Drug Actions in Man Volume 7 Principles of Behavioral Pharmacology

Edited by Leslie L. Iversen Department of Pharmacology University of Cambridge Susan D. Iversen Department of University of Cambridge and Solomon H. Snyder Departments of Pharmacology and The Johns Hopkins University School of

PLENUM PRESS • NEW YORK AND LONDON Library of Congress Cataloging in Publication Data Main entry under title: Handbook of psychopharmacology. Includes bibliographies and indexes. CONTENTS: v. 1. Biochemical principles and techniques in neuropharmacology. -v. 2. Principles of receptor research.-v. 3. Biochemistry of biogenic amines.-v. 4. Amino acid neurotransmitters.-v. 5. Synaptic modulators.-v. 6. Biogenic amine receptors.-v. 7. Principles of behavioral pharmacology. 1. Psychopharmacology. I. Iversen, Leslie Lars. II. Iversen, Susan D., 1940- III. Snyder, Solomon H., 1938- [DNLM: 1. Psychopharmacology. QV77 H236j RC483.H36 615.78 75-6851 lSBN-13: 978-1-4613-4216-8 e-lSBN-13: 978-1-4613-4214-4 DOl: 10.1007/978-1-4613-4214-4

© 1977 Plenum Press, New York Softcover reprint of the hardcover 1st edition 1977 A Division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. 10011

All rights reserved

No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written pennission from the Publisher CONTRIBUTORS TO VOLUME 7

P. L. BROADHURST, Department oj Psychology, University oj Birmingham, Birming• ham, England BYRON A. CAMPBELL, Department oj Psychology, Princeton University, Princeton, New Jersey M. R. A. CHANCE, Sub-Department oj Ethology, University oj Birmingham, Birmingham, England P. B. DEWS, Laboratory oj Psychobiology, Department oj Psychiatry, Harvard Medical School, Boston, Massachusetts Jo DEWEESE, Laboratory oj Psychobiology, Department of Psychiatry, Harvard Medical School, Boston, Massachusetts R. T. KELLEHER, Haroard Medical School, New England Regional Primate Research Center, S01Jihborough, Massachusetts R. KUMAR, Institute oj Psychiatry, De Crespigny Park, London, England PAUL D. MABRY, Department oj Psychology, Princeton University, Princeton, New Jersey J. H. MACKINTOSH, Sub-Department oj Ethology, University oj Birmingham, Birmingham, England JOHN F. MARSHALL, The Psychobiology Program, Departmer/Js oj Psychology and Psychiatry, University oj Pittsburgh, Pittsburgh, Pennsylvania J. W. McKEARNEY, Worcester FourukJJion for Experimental Biology, Shrewsbury, Massachusetts PETER M. MILNER, Department oj Psychology, McGiU University, Montreal, Quebec, Canada W. H. MORSE, Laboratory oj Psychobiology, Haroard Medical School, Boston, Massachusetts STATA NORTON, Department oj Pharmacology and Ralph L. Smith Mental Retardation Research Center, University oj Kansas Medical Center, Kansas City, Kansas T. W. ROBBINS, Psychological Laboratory, University oj Cambridge, Cambridge, England

v vi CONTRIBUTORS TO VOLUME 7

A. P. SILVERMAN, Central Laboratory, Imperini Chemical Industries Ltd., Alderley Park, Cheshire, England 1. P. STOLERMAN, MRC Neuropharmacology Unit, The Medical School, Birming• ham, England PHILIP TEITELBAUM, Department of Psychology, University oj Illinois, Champaign, Illinois LUIGI V ALZELLI, Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy PREFACE

The first six volumes of the Handbook reviewed basic neuropharmacology, drawing on expertise in biochemistry, pharmacology and . The next three volumes focus attention on the functional importance of these basic neuropharmacological mechanisms for normal behavior. In order to study this interface in the intact functioning organism, appropriate methods for describing and quantifying behavior must be developed. The past twenty years have witnessed a revolution in the study of behavior which has taken us away from the often fruitless theoretical arguments to descriptive . Technical achievements in the design of apparatus and the recording of behavior played an important role in these developments, and the resultant behavioral methods have been accepted and found useful in studying the effects of drugs. The development of psycho• pharmacology as a discipline owes as much to these behavioral methods as it does to the basic neuropharmacological techniques pioneered for in vitro studies. In the first section of Volume 7, an effort has been made to provide reviews both of theory and practice in behavioral science. Milner's chapter deals with the concept of motivation in a theoretical framework. By contrast, the chapters by Morse et al. and Dews and DeWeese provide a more descriptive view of the various ways in which aversive stimuli control behavior and the importance of schedules of in determining the profile of responding in the animal. The equal importance of observational behav• ioral methods is well illustrated by Mackintosh et al., and a more detailed treatment of the analysis of sequences of behavior is provided by Norton. Other contributors illustrate how a variety of these behavioral approaches and methods may be combined in the analysis of a particular problem. Marshall and Teitelbaum do this admirably for motivation, and Kumar discusses the progress that has been made in developing animal models of certain human behavioral disorders. In the remaining section of Volume 7, attention is paid to the general factors that determine the proftle of behavioral responses in the individual and their potential for modification by drugs. This represents an immensely

VII viii PREFACE important and growing area in psychopharmacology. Genetic factors, devel• opmental experience, social experience, and drug experience have been selected for review. Global descriptions of behavior often seem far removed from the detailed workings of brain neuropharmacology. In Volume 8 this chasm is bridged. In some areas we are beginning to understand how function at the neuronal level is related to overt behavior. This is so in the case of eating, drinking, sex, sleep, and memory, and the volume provides reviews in these areas. Certain areas, however, remain highly controversial, and it was consid• ered important to represent the unresolved as well as the resolved issues. The neural and neuropharmacological basis of reinforcement is one such problem, and Routtenberg and Stein et ai. provide provocative reviews from two points of view. An effort has also been made to include reference to more diffuse areas of behavioral control such as behavioral inhibition. Warburton and Gray review this topic from different theoretical positions and illustrate how difficult it is to devise specific behavioral tests for certain nervous functions. Yet it may be that these more global levels of control al e of immense importance in behavioral integration. Finally, in Volume 9 the structural basis of neuropharmacology is considered. Are neuropharmacological systems, for example, a particular class of receptor or , localized in the brain? And if so, how do we go about unraveling the details of this organization? Histochemical techniques for localizing acetylcholine, , and indoleamine path• ways in the brain are reviewed and information presented on our current knowledge of the anatomical distribution of these transmitter pathways in the central . Alternative methods using radioautography and immunofluorescence are also considered. These techniques are already proving to be of immense importance in studying neurotransmitter localiza• tion at the neuronal level and, in particular, in the study of novel neuromo• dulators such as the peptides, where conventional histochemical methods are not available. Lesion techniques have traditionally played an important role in unraveling neural organization and continue to do so in conjunction with the specific histological techniques. The problems associated with lesion techniques are also considered. This volume is a fair reflection of the current state of knowledge regarding the anatomical basis of neuropharmacology and is invaluable to those seeking to understand the basis of behavior and its modification of psychotropic drugs.

L.L.1. S.D. I. S.H.S. CONTENTS

METHODS FOR STUDYING UNCONDITIONED AND CONDITIONED BEHAVIOR

CHAPTER 1 The Contribution of Ethological Techniques to the Study of Drug Effects J. H. MACKINTOSH, M. R. A. CHANCE, and A. P. SILVERMAN

1. Introduction ...... 3 2. Behavior of Laboratory Rodents ...... 5 2.1. Exploration ...... 6 2.2. Eating and Drinking ...... 6 2.3. Digging and Nest-Building ...... 7 2.4. Social Behavior ...... 7 2.5. Analysis of Behavior ...... 10 2.6. Social Structure ...... 15 3. Pharmacological Investigations ...... 17 3.1. ...... 17 3.2. Ethyl Alcohol ...... 18 3.3. ...... 20 3.4. Trichloroethylene Vapor ...... 22 3.5. ...... 22 4. Effect of Olfactory Signals on Behavior ...... 25 5. Ethological Methods in Clinical Drug Trials ...... 28 6. Discussion ...... 29 7. References ...... 31

ix x CONTENTS

CHAPTER 2 A Critique of the Methods Available for the Measurement of Spontaneous Motor Activity T. W. ROBBINS 1. Introduction ...... 37 2. Methods of Measuring Locomotor Activity ...... 38 2.1. Photocell Cages ...... 39 2.2. Running Wheels...... 40 2.3. Stabilimeters and Jiggle Cages ...... 40 2.4. Tilt Cages ...... 41 2.5. Open Fields ...... 41 2.6. Direct ...... 43 3. Internal and External Factors That Affect Activity ...... 47 3.1. Baseline Levels of Activity ...... 48 3.2. Internal Factors ...... 50 3.3. External Factors ...... 55 4. Statistical Analysis of Results ...... 57 4.1. Locomotor Activity ...... 57 4.2. Rating Scales ...... 58 5. Combining Modes of Measurement ...... 63 6. Exploration and Its Measurement ...... 64 6.1. Introduction ...... 64 6.2. Methodological Considerations ...... 65 6.3. Conclusions ...... 75 7. References ...... 77

CHAPTER 3 The Study of Sequences of Motor Behavior STATA NORTON 1. Introduction ...... 83 2. The Organization of Behavior ...... 85 2.1. Sequences of Behavior (Behavior Patterns) ...... 87 2.2. Interval Histograms of Acts ...... 93 2.3. Duration of Acts ...... 94 2.4. Frequency of Acts ...... 96 2.5. The Motor Act ...... 97 2.6. Conclusions ...... 98 3. Methods of Analysis ...... 99 3.1. Environmental Factors ...... 99 3.2. Data-Recording...... 100 3.3. Reliability of Observers ...... 101 CONTENTS xi

4. Examples and Results ...... 102 4.l. Continuous Recording ...... 102 4.2. Time-Sampling Methods ...... 103 4.3. Stereotyped Behavior ...... 103 5. Summary ...... 104 6. References ...... 105

CHAPTER 4 Schedules of Reinforcement P. B. DEWS andJo DEWEESE 1. Introduction ...... 107 2. Some Schedule Effects ...... 109 2.l. Schedules and Programs ...... 109 2.2. Responses ...... III 2.3. S(D) T x sec Nl S(rf) (Program of FI Schedules) .... 112 2.4. S(D) N n S(rf) (Program of FR Schedules) ...... 115 2.5. S(D1) T x sec N 1 S(rf), S(D 2) N n S(rf) (Program of a mult FI, FR Schedule) ...... 117 2.6. S(D) [T x sec S(p) or Nl T Y sec S(p)] ...... 119 2.7. S(D) N n S(rf) and N ii' S(p) ("Punishment") ...... 121 2.8. Transitional States ...... 122 3. Behavioral Pharmacology ...... 123 3.l. Schedules of Reinforcement in Behavioral Pharmacology ...... 124 3.2. How to Express Drug Effects ...... 127 3.3. Effects of Drugs on Responding under FI and FR .. 128 3.4. Effects of Drugs on Responding under Postponement Schedules and Schedules of Suppression ...... 135 3.5. Summary ...... 143 4. What Do Drugs Affect When They Affect Behavior? .... 143 5. References ...... 146

CHAPTER 5 Control of Behavior by Noxious Stimuli W. H. MORSE, J. W. McKEARNEY, and R. T. KELLEHER l. Introduction ...... 151 1.1. Behavioral Processes That Can Be Controlled by Noxious Stimuli ...... 152 l.2. Characteristics of Events That Modify Behavior .... 153 l.3. Use of Electric Shock in Behavioral Experiments ... 154 xii CONTENTS

2. Schedules Using Noxious Stimuli to Maintain Behavior 155 2.1. Behavior Maintained by the Termination of Noxious Stimuli (Escape) ...... 155 2.2. Behavior Maintained by the Postponement of Noxious Stimuli (Avoidance) ...... 157 2.3. Behavior Maintained by the Presentation of Noxious Stimuli ...... 159 3. Effects of Drugs on Behavior Maintained by Noxious Stimuli and Other Events ...... 162 4. Behavior Suppressed by Noxious Stimuli (Punishment) .. 169 4.1. Behavior Maintained by Food or Water Presentation 170 4.2. Behavior Maintained by, or in the Context of, Schedules of Electric Shock Termination, Postponement, or Presentation ...... 172 5. Summary and Conclusions ...... 175 6. References ...... 177

CHAPTER 6 Theories of Reinforcement, Drive, and Motivation PETER M. MILNER 1. Introduction ...... 181 2. Reinforcement...... 182 3. Cognitive Learning Theories ...... 185 3.1. McCorquodale and Meehl's Expectancy Theory .... 186 3.2. Drive-Initiated Behavior ...... 187 3.3. Attention ...... 188 3.4. Criteria for Overt Responses ...... 189 3.5. Motivation ...... 190 4. Physiological Interpretation of the Expectancy Model .... 191 5. Self-Stimulation ...... 194 6. Responses to Aversive Stimuli ...... 196 7. Conclusion ...... 198 8. References ...... 199

CHAPTER 7 New Considerations in the of Motivated JOHN F. MARSHALL and PHILIP TEITELBAUM 1. Introduction ...... 201 2. The Lateral Hypothalamic Syndrome...... 202 2.1. Impairments in Food and Water Intake ...... 202 2.2. Sensorimotor Impairments ...... 204 2.3. Activational Changes ...... 209 CONTENTS xiii

3. The Ventromedial Hypothalamic Syndrome ...... 212 4. Selective Lesion Technique: The Lateral Hypothalamic Syndrome ...... 215 5. Clinical Disorders of Movement Involving Brain 217 6. Levels of Control over Behavior ...... 220 7. Conclusions ...... 222 8. References ...... 224

CHAPTER 8 Animal Behavioral Models of Relevance to Psychiatry R. KUMAR 1. Introduction ...... 231 2. Animal Models of Some Psychiatric Disorders ...... 237 2.1. Schizophrenic Disorders ...... 237 2.2. Manic-Depressive Disorders ...... 240 2.3. Fear and Anxiety ...... 247 3. General Comments...... 252 4. References ...... 253

FACTORS THAT INFLUENCE BEHAVIORAL RESPONSES TO DRUGS

CHAPTER 9 Pharmacogenetics P. L. BROADHURST 1. Introduction ...... 265 2. Sex Differences ...... 266 3. Selection ...... 269 3.1. Pharmacogenetic Selection ...... 269 3.2. Other Selections ...... 274 4. Strain Differences ...... 285 4.1. Variability of Response ...... 285 4.2. Amphetamine and Other Stimulants ...... 286 4.3. Diallel Cross ...... 286 4.4. Tranquilizers ...... 292 4.5. and Convulsants ...... 293 4.6. Recombinant Inbred Strains ...... 295 4.7. Alcohol and Opiates ...... 298 5. Summary and Conclusions ...... 304 6. References ...... 305 XIV CONTENTS

CHAPTER 10 Experimental and Clinical Aspects of Drug Dependence R. KUMAR and I. P. STOLERMAN 1. Introduction ...... 321 2. Epidemiological Approaches ...... 324 2.1. Prevalence Studies ...... 325 2.2. Retrospective Studies ...... 327 2.3. Prospective Studies ...... 328 3. Experimental Analyses of Drug-Taking Behavior ...... 329 3.1. Positive Primary Reinforcement ...... 329 3.2. Positive Secondary Reinforcement ...... 337 3.3. Aversive Control ...... 339 3.4. Discriminative Control by Drugs ...... 342 3.5. Role of Adjunctive Behavior ...... 343 4. , Learning, and Memory ...... 346 4.1. Critique of Learning Factors in Tolerance ...... 346 4.2. Proposed Criteria ...... 348 4.3. Parallels Between Tolerance and Memory ...... 349 5. Treatment of Drug Dependence ...... 350 5.1. Enforced Abstinence ...... 350 5.2. Psychological and Social Rehabilitation ...... 352 5.3. Controlled Prescription and Maintenance ...... 352 5.4. Pharmacological Antagonists ...... 353 5.5. Aversive Control ...... 355 5.6. ...... 355 5.7. General Principles of Management ...... 356 6. References ...... 357

CHAPTER 11 Social Experience as a Determinant of Normal Behavior and Drug Effect LUIGI VALZELLI 1. Introduction ...... 369 2. Environment and Brain Evolution ...... 371 3. Subject-Environment Interaction ...... 372 4. Socioenvironmental Impoverishment ...... 373 5. Socioenvironmental Deprivation (Isolation) ...... 373 6. Psychotropic Drug Activity ...... 375 7. The Limbic System and Emotional Behavior ...... 379 8. Socioenvironmental Enrichment ...... 380 9. Conclusions ...... 381 10. References ...... 382 CONTENTS xv

CHAPTER 12 Developmental Psychopharmacology PAUL D. MABRY and BYRON A. CAMPBELL 1. Introduction ...... 393 2. Neurochemical Development ...... 394 2.1. The Monoamines ...... 395 2.2. Acetylcholine ...... 405 3. Developmental Drug Effects ...... 407 3.1. Drugs That Act Selectively on the Monoamines ..... 408 3.2. Drugs That Act Selectively on Acetylcholine ...... 432 4. Conclusions ...... 435 5. References ...... 436

Index...... 445