National Institute on Drug Abuse MONOGRAPH SERIES Problems of Drug Dependence 1981 Proceedings of the 43rd Annual Scientific Meeting The Committee on Problems of Drug Dependence, Inc. Printed by The Committee on Problems of Drug Dependence, Inc. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration Problems of Drug Dependence, 1981 Proceedings of the 43rd Annual Scientific Meeting, The Committee on Problems of Drug Dependence, Inc. Editor: Louis S. Harris, Ph.D. NIDA Research Monograph 41 April 1982 DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National lnstltute on Drug Abuse Division of Research 5600 Fishers Lane Rockville, Maryland 20857 Printed by The Committee on Problems of Drug Dependence, Inc. The NIDA Research Monograph series is prepared by the Division of Research of the National Institute on Drug Abuse. Its primary objective is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, integrative research reviews and significant original research its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. Editorial Advisory Board Avram Goldstein, M.D. Addiction Research Foundation Palo Alto, California Jerome Jaffe, M.D. University of Connecticut School of Medicine Farmington, Connecticut Reese T. Jones, M.D. Langley Porter Neuropsychiatric Institute University of California San Francisco, California Jack Mendelson, M.D. Alcohol and Drug Abuse Research Center Harvard Medical School McLean Hospital Belmont, Massachusetts Helen Nowlis, Ph.D. Rochester, New York Lee Robins, Ph.D. Washington University School of Medicine St. Louis, Missouri NIDA Research Monograph series William Pollin, M.D. DIRECTOR, NIDA Marvin Snyder, Ph.D. DIRECTOR, DIVISION OF RESEARCH, NIDA EDITOR-IN-CHIEF Eleanor W. Waldrop MANAGING EDITOR Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857 Problems of Drug Dependence, 1981 Proceedings of the 41st Annual Scientific Meeting The Committee on Problems of Drug Dependence, Inc. MEMBERS, COMMITTEE ON PROBLEMS OF DRUG DEPENDENCE, INC. Dr. Joseph Cochin, Chairman Dr. Joseph Brady Dr. Troy Duster Dr. Charles Gorodetzky Dr. Louis Harris Dr. Theresa Harwood Dr. Arthur Jacobson Dr. Jerome Jaffee Dr. Arthur Keats Dr. Harold Kalant Or. Everette May Dr. Jack Mendelson Dr. C. R. Schuster Dr. Henry Swain EXECUTIVE SECRETARY Dr. Leo Hollister MEMBERS, BOARD OF DIRECTORS Dr. W. L. Way, Chairman Am. Soc. Pharmacol. Exptl. Ther. Dr. D. X. Freedman Am. Psychiatric Assn. Dr. K. F. Killam Am. Coll. Neuropsychopharmacol. Dr. Everette May Am. Chemical Society Dr. Edward C. Senay Am. Medical Assn. Dr. Beny J. Primm National Medical Assn. Dr. James Woods Am. Psychological Assn. Dr. Raymond W. Houde Am. Soc. Clin. Pharmacol. Ther. MEMBERS, PROGRAM COMMITTEE Dr. Louis S. Harris, Chairman Dr. Everette L. May Mrs. Joyce H. Pye MEMBERS, COMMITTEE ON ARRANGEMENTS Dr. E. L. Way, Chairman Dr. K. F. Killam Dr. L. E. Hollister Acknowledgment The papers in this monograph were presented or read by title at the 43rd Annual Scientific Meeting of the Committee on Problems of Drug Dependence, Inc., in San Francisco, California, on July 12-15, 1981. All material appearing in this volume is in the public domain and may be reproduced or copied without permission from the National Institute on Drug Abuse or the authors. Citation of the source is appreciated. The United States Government does not endorse or favor any specific commercial product or commodity. Trade or proprietary names appearing in this publication are used only because they are considered essential in the context of the studies reported herein. Library of Congress catalog card number 82-600540 Printed 1982 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of the American Statistics Index, BioSciences Information Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharma- cology Abstracts. V CONTRIBUTING FIRMS, 1980-81 The following firms have supported the work of the Committee on Problems of Drug Dependence, Inc., through contributions during the previous fiscal year. Abbott Laboratories Boehringer Ingelheim International Bristol Laboratories Burroughs Wellcome Company Chemie Linz AG Clin-Midy of America, Inc. Endo Laboratories, Inc. (DuPont) Hoechst-Roussel Pharmaceuticals, Inc. Hoffman-La Roche, Inc. ICI Americas, Inc. Knoll Pharmaceutical Company Lederle Laboratories (Cyanamid) Lilly Research Laboratories McNeil Pharmaceutical Mead Johnson Pharmaceutical Division Merck Sharp & Dohme Research Labs Merrell Dow Pharmaceuticals, Inc. Miles Laboratories, Inc. Ortho Pharmaceutical Corporation Pennwalt Corporation Pharmaceutical Division Pfizer Central Research Reckitt & Colman Pharmaceutical Division A. H. Robins Company Sandoz, Ltd. (Basle) Sandoz, Inc. (New Jersey) Searle Research & Development SISA, Incorporated Smith Kline & French Laboratories E. R. Squibb & Sons, Inc. Sterling Drug, Inc. The Upjohn Company USV Pharmaceutical Corporation (Revlon) Wyeth Laboratories vi Foreword For more than a half century, the Committee on Problems of Drug Dependence has played a distinguished part in research on drugs that affect the central nervous system. It has served as a catalyst and bonding agent for the work of academic researchers, governmental and international organizations, and the pharmaceu- tical industry while also conducting its own programs to eval- uate the efficacy and dependence liability of new compounds. The broad range of CPDD interests is reflected in the diversity of its membership: chemists and biochemists, pharmacologists, physicians, psychologists, sociologists, and others share in its endeavors. The 43rd Annual Scientific Meeting of the Committee on Problems of Drug Dependence was held in San Francisco on July 12-15, 1981. Characteristically, a broad and stimulating program of informa- tion and ideas was presented. Probably no other single meeting covers current research in drug abuse so comprehensively. For the third year, the National Institute on Drug Abuse is pleased to present the CPDD proceedings in its, Research Monograph series. William Pollin, M.D. Director National Institute on Drug Abuse vii Abraham Wikler, M.D. viii In Memoriam: Abraham Wikler, M.D. Abraham Wikler died on March 7, 1981, in Lexington, Kentucky where he had lived and worked for more than forty years. He was 70 years old. His wife, Ada, as always, was at his side. Abe Wikler's scientific work has had a direct and profound influence on our current understanding of drug dependence and on the lives and careers of many of us in this room. My own entry into the field of psychiatry and psychopharmacology was directly attributable to the reading of Abe's 1957 review article and monograph, The Relation of Psychiatry to Pharmacology. Abe's career in psychiatry began with a residency training at the Hospital at Lexington. Following this he was asked by Clifton Himmelsbach, in 1942, to set up an experimental neuropsychiatry laboratory in the Research Department. Calling on the neurophysi- ological techniques that he had acquired from Fulton at Yale, Lloyd at the Rockefeller Institute, and the familiarity with Pavlovian thought that he acquired while studying with Wasserman at North- western, Abe began to focus on the nature of physical dependence, drug seeking behavior, and the basis of relapse. In the process, he was able to demonstrate that physical dependence was not merely a "psychic" phenomenon and that there were physiological changes at all levels of the CNS accompanying it. Further, by using nalor- phine, he demonstrated that such changes could develop early in the course of drug use. In fact, Abe, Harris Isbell and Nathan Eddy were the first to demonstrate nalorphine-precipitated withdrawal in opiate dependent humans. Abe recognized that these changes could not explain relapse many months after withdrawal of drugs. Abe's clinical acumen led him to postulate that the recurrence of abstinence phenomena when addicts talked about drugs or returned to environments associated with drug taking was due to conditioning, in which the stimuli associated with withdrawal symptoms and with positive drug effects came to elicit these effects as conditioned responses long after the drug had been withdrawn. He also postulated that the withdrawal phenomena which ix develop early in the course of use provide a regularly recurring motive that permits the addict to work, or "hustle," for an immediate reward - the alleviation of withdrawal distress. Thus, "hustling" to obtain drugs, with its repeated immediate reinforce- ment, strengthened the drug taking behavior even as it served to alleviate the addict's boredom and even the hustling could become a conditioned response. Then, in a long series of experiments involving rats, Abe was able to demonstrate that a conditioning process which develops during opiate use increases the likelihood of opiate self-administration for months after withdrawal. This view of addiction as a process involving learning and con- ditioning, which Abe was one of the first to champion, has now been accepted as a fundamental aspect of our understanding of drug dependencies and relapse and led, in Abe's lifetime, to a number of distinct approaches to both opiate and alcohol dependence based on these ideas. For these and other contributions,