Discriminative Stimulus Properties

of Drugs

ADVANCES IN BEHAVIORAL BIOLOGY

Editorial Board:

Jan Bures Irwin Kopin Bruce McEwen James McGaugh Karl Pribram

Institute of Physiology, Prague, Czechoslovakia National Institute of Mental Health, Bethesda, Maryland Rockefeller University, New York, New York University of California, Irvine, California

Jay Rosenblatt Lawrence Weiskrantz

Stanford University School of Medicine, Stanford, California Rutgers University, Newark, New Jersey University of Oxford, Oxford, Eng/and

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Volume 20 • THE SEPTAL NUCLEI Edited by Jon F. DeFrance. 1976

Volume 21 • COCAINE AND OTHER STIMULANTS Edited by Everett H. Ellinwood, Jr. and M. Marlyne Kilbey .1977

Volume 22. DISCRIMINATIVE STIMULUS PROPERTIES OF DRUGS Edited by Harbans Lal • 1977

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Discriminative Stimulus Properties

of Drugs

Edited by

Harbans Lal University of Rhode Island, Kingston

PLENUM PRESS· NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

Main entry under title:

Discriminative stimulus properties of drugs.

(Advances in behavioral biology; v. 221 Includes index. 1. Psychopharmacology. 2. Drugs-Physiological effect. 3. Drugs-Psychological

aspects. I. Harbans Lal. [DNLM: 1. Drugs. QV38 D449] RM31S.DS8 61S'.78 77·180S

ISBN-13: 978-1-4684-3092-9 e-ISBN-13: 978-1-4684-3090-5 DOl: 10.1007/978-1-4684-3090-5

© 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,

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Foreword

As one who has gone down the wayward path from "pure" organic chemistry to biochemistry to pharmacology, I was not quite prepared to go all the way - into the field of discriminable stimuli. The organizer of the symposium on discriminable stimuli induced by drugs, Dr. Harbans Lal, did seduce me into attending. Having lost my behavioral virginity, I now stare with open eyes at the field. One item in particular at this meeting exemplifies to me the power of such techniques. Dr. Albert Weissman mentioned the problem he tackled with getting rats to discriminate between saline and dilute solutions of aspirin. Under ordinary circumstances, the animals could not perform this task. However, if the animals were sensitized by injection of prostaglan­din into their foot pads, then they were capable of discriminating even very dilute solutions of aspirin. In a sense, Al had created a model of the human arthritic who can jolly well tell if you have given him an aspirin or a salt tablet.

The reader of this volume will find it a good introduction to the utilization of discriminable stimuli induced by drugs. After a preface by the organizer, two experts discuss basic principles in separate chapters. One of these chapters places emphasis on the drugs; the other places emphasis on the induced cues and states. As a concluding chapter, there is a summary of past research in the field as well as speculation on the future. These speculations have value since they are made by one of the long-term workers in the field: Dr. Lal.

Between the introduction and the summary, there are chapters on a number of classes of psychotropic drugs which have been studied with regard to discriminable stimuli: narcotic analgesics, narcotic antagonists, marihuana, alcohol and othe r CNS depre s­sants, nicotinic drugs, hallucinogens, psychomotor stimulants, benzodiazepines. Clearly the emphasis is more on abused drugs than on psychotherapeutic drugs, but my prediction is that the technique will be applied increasingly to the study of psycothera­peutic drugs. This latter application may require the preconditioning of animals (similar to that in the aspirin study).

v

vi FOREWORD

In one chapter, that of Altman et, al., there is a summary of human studies using drugs as discriminative events. Undoubtedly such human studies will also be an area of increasing importance in the near future. This chapter and its excellent bibliography should serve as a good base for clinical applications.

All in all, I found the meeting fascinating and useful and I would not be surprised if many a reader found this volume similarly fascinating and useful.

Earl Usdin, Ph. D. Chief Pharmacology Section National Institute of Mental Health

Preface

Availability of drugs has long been a bonanza to researchers in many fields. But in the field of behavioral biology and behavior­al medicine it has played a particularly critical role. With drugs, researchers have been able to tease out behavioral processes and disease states for understanding their mechanisms which have otherwise defied investigation. The biochemical changes that drugs produce in the brain and the changes which are then reflected in neurophysiology and in altered states of behavior are measured quite reliably as unconditional and conditional responses. This chain of events specifically induced by drugs provides a unique system for scientific study of interdependent biological processes. Drug effects are readily reversible and can be replicated with reliability.

Drugs can be considered as a class of stimuli with properties so complex and varied that conventional stimuli such as light and i3ound, no matter how complex, seem to be barren by comparison. Drugs provide stimuli of many kinds. Their acute actions are often considered as unconditional stimuli. Some drugs serve as positive or negative reinforcers. Recently, a few drugs have been found to serve as conditional stimuli, a finding which has greatly facilitated understanding of placebo effects.

The present book extensively reviews a newly recognized function of drugs; namely their ability to act as discriminative stimuli. When a pharmacological action is psychologically perceived a drug is said to have formed a discriminative stimulus. In this case the focus is not on what the drug doe s to the subje ct, but rather on how the subject's behavior reflects his realization that drug is acting in his body. What is innovative in this is that, whereas in the past discrimination studies have always utilized externally presented physical events as stimUli, now the changes in the inte rnal state of the subje ct be come the focus of dis c rimina­tion studies. This discovery led a number of researchers to design experiments in which they ask questions such as "Which drugs can and which cannot produce a discriminative stimulus?" and "When a drug is established as a discriminative stimulus,

vii

viii PREFACE

which drugs or physiological manipulations do and which do not generalize to this stimulus? 11 These questions are researched because they have implications in both basic and applied fields. Which effects of drugs provide the basis for drug discrimination? Can a peripherally acting effect of a drug be discriminated? Can stimulation or lesioning of selected brain areas generalize to or antagonize the drug stimuli? What are the rules under which drug discrimination is acquired or extinguished? Are drug stimuli related to the therapeutic effects?

There are many applied implications of drug-induced dis­criminable stimuli just as there are basic implications. Drug discrimination is already being looked intofor its potential in providing a tool for the study of interoceptive stimuli, for study of chemical bases of euphoria, to develop animal models of disease states, to investigate biochemistry of mood alteration, and to establish new ways of predicting therapeutic as well as toxic effects of newly synthesized chemicals. Already drug discrimination data are being routinely utilized in decision making at early stages of drug development.

All of the above questions are reviewed for the first time in one volume by scientists who themselves pioneered research in this area. In addition, material compiled by one scientist is strengthened and modified by feedback from other scientists. Before each chapte r of this book was complet ed, all of the authors were invited for a weekend retreat in New Hampshire to review together the contents of various chapters. Through this process ideas and suggestions generated out of collective thinking we re incorporated in the final version of the manuscripts.

A glance over the contents of this book will reveal that the subject of drug discrimination has been treated rather extensively by the leaders in the field. Individual chapters examined dis­criminative stimuli formed by different classes of drugs. They also examine theoretical aspects of this newly emerging field of scientific inquiry. Applications of drug discrimination in broad areas of physiology, psychology, psychiatry, pharmacology, neurochemistry and medicine are discussed throughout the book. New approaches to drug development and animal models of human disease s are elaborated.

Psychologists, psychiatrists, pharmacologists and physiolO­gists, whether in research or teaching, will find this book valuable. Also, graduate students in behavioral and medical sciences can benefit. This book will serve as a ready reference for pharma­cologists, toxicologists, and chemists in pharmaceutical industry.

PREFACE

They can refe r to this book for details of methodology and already available information applicable in drug development as all of the chapters are replete with actual data and illustrations. Because of the rapid publication of the book, the material is fresh and updated. The book was prepared with these objectives in mind. If these goals are accomplished I feel highly compensated for my efforts in putting this book together.

January 28, 1977 Harbans La1

ix

Acknowledgments

I wish to express my sincere gratitude and appreciation to the many friends and coworkers who have given of their time, effort and encouragement in the preparation of this volume. Many others inter­acted in numerous ways in perceiving and organizing concepts which are elaborated in this book. Even though it is impossible to acknow­ledge all of those who have contributed, I do wish to cite the fol­owing people for their support.

Dr. Paul Janssen made his laboratories available and Dr. Carlos Niemegeers and Hr. Francis Colpaert were team-mates in generating many data and concepts included in this book. Dr. Stuart Feilding, Dr. William J. Novik, Dr. David Tedeschi, and Dr. Albert Weissman provided encouragement and assistance in obtaining funds. Mary Alyce Conrad, Lucie A. Johnson and Kathleen HcGovern carefully typed por­tions of the manuscript. Secretarial services were amply provided by Elda G. Pellerin. Dr. Gerald Gianutsos and Dr. Nelson Smith assi~ ted in editorial work and Stephen Hiksic proofread the material. Robert Gianforcaro, Gary Shearman and Stephen Hiksic prepared the subject index. Lederle Laboratories, Hoescht-Roussell Pharmaceutical Inc., Pfizer, Inc., and Coulbourn Instrument Co. provided financial support. The staff of New England Center for Continuing Education provided excellent services during the meeting of contributors to finalize the material included in this manuscript. Dr. Earl Usdin of the National Institute of Hental Health was instrumental in ar­ranging the publication of the abstracts in Psychopharmacological Communications.

I especially thank the contributors without whose timely support and excellent coverage of the material this boook could have never been completed. Appreciation is also due to the many investigators and publishers who generously gave permission to the authors to re­produce parts of their material.

Finally, a special acknowledgement is given to Plenum Press and its staff for their patience and helpful collaboration.

x

Contents

Drugs as Discriminative Stimuli • • • • • • • • • • • • • • •• 1 Albert Weissman

Drug-Induced Cues and States: Some Theoretical and Methodological Inferences • • • • • • • • • •• 5

Francis C. Colpaert

Discriminable Stimuli Produced by Narcotic Analgesics .. • " , • " • • • • • • • • • • • . • , •. 23

Harbans Lal, Gerald Gianutsos, and Stephen Miksic

Discriminative Properties of Narcotic Antagonists . . . " . 11 " " " • , , " • .. " "

Stephen G. Holtzman, Harlan E. Shannon, and Gerald J. Schaefer

Discriminable Stimuli Produced by Alcohol and Other CNS Depressants ; • • • • • • •

Herbert Barry III and Edward C. Krimmer

Discriminative Stimulus Properties of Benzodiazepine and Barbiturates

Francis C. Colpaert

Characterization of Discriminative Response Control by Psychomotor Stimulants •

Peter B. Silverman and Beng T. Ho

Discriminable Stimuli Produced by Marihuana Constituents ••••

Edward C. Krimmer and Herbert Barry III

Discriminative Stimulus Properties of Hallucinogens: Behavioral Assay of Drug Action . . • • .. .. • " .. "

Donald M. Kuhn, Francis J. White, and James B. Appel

xi

47

73

93

107

III .. " .. .. " .. " " 121

137

Cholinergic and Non-Cholinergic Aspects of the Discriminative Stimulus Properties'of Nicotine • • • • • . • • • • • • • •

John A. Rosecrans and William T. Chance . . . . . . . . .

Drugs as Discriminable Events in Humans • • • Jack L. Altman. Jean-Marie Albert. Stephen L. Milstein, and Isaac Greenberg

Drug-Induced Discriminable Stimuli: Past Research and Future Perspectives

Harbans La1 • • • • • • • • t • t •

Index • • • . . . . . . . . . . . . . . . . . . . . . . . . .

CONTENTS

155

187

207

233