National Institute on Drug Abuse MONOGRAPH SERIES Problems of Drug Dependence 1986 Proceedings of the 48th Annual Scientific Meeting 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, 1986 Proceedings of the 48th Annual Scientific Meeting, The Committee on Problems of Drug Dependence, Inc. Editor: Louis S. Harris, Ph.D. NIDA Research Monograph 76 1987 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse Office of Science 5600 Fishers Lane Rockville, Maryland 20857 NIDA Research Monographs are prepared by the research divisions of the National Institute on Drug Abuse and published by its Office of Science. The primary objective of the series is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, and integrative research reviews. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. Editorial Advisors MARTIN W. ADLER, Ph.D. SIDNEY COHEN, M.D. Temple University School of Medicine Los Angeles, California Philadelphia, Pennsylvania SYDNEY ARCHER, Ph.D. MARY L. JACOBSON Rensselaer Polytechnic Institute National Federation of Parents for Troy, New York Drug-Free Youth RICHARD E. BELLEVILLE, Ph.D. Omaha, Nebraska NE Associates. Health Sciences Rockville, Maryland REESE T. JONES, M.D. KARST J. BESTEMAN Langley Porter Neuropsychiatric Institute Alcohol and Drug Problems Association San Francisco, California of North America Washington, D.C. DENISE KANDEL, Ph.D. GILBERT J. BOTVIN, Ph.D. College of Physicians and Surgeons of Cornell University Medical College Columbia University New York, New York New York, New York JOSEPH V. BRADY, Ph.D. The Johns Hopkins University School of HERBERT KLEBER, M.D. Medicine Yale University School of Medicine Baltimore, Maryland New Haven, Connecticut THEODORE J. CICERO, Ph.D. Washington University School of RICHARD RUSSO Medicine New Jersey State Department of Health St. Louis, Missouri Trenton, New Jersey NIDA Research Monograph Series CHARLES R. SCHUSTER, Ph.D. Director, NIDA JEAN PAUL SMITH, Ph.D. Acting Associate Director for Science. NIDA Acting Editor Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857 Foreword The National Institute on Drug Abuse (NIDA) is pleased to publish in its Research Monograph series the proceedings of the 48th Annual Scientific Meeting of the Committee on Problems of Drug Dependence, Inc. (CPDD). This meeting was held at Tahoe City, Nevada, in June 1986. The scientific community working in the drug abuse area was saddened by the untimely death of one of its very productive and active leaders: Joseph Cochin, M.D., Ph.D. Joe was a talented scientist who was greatly admired by his students and colleagues. For the past five years, Joe had served as the Executive Secretary of the CPDD. This monograph includes papers from a symposium on "Mechanisms of Opioid Tolerance and Dependence," dedicated to his memory. These papers were presented by many of his friends and colleagues, who took the opportunity to express their high esteem for Joe. The CPDD is an independent organization of internationally recognized experts in a variety of disciplines related to drug addiction. NIDA and the CPDD share many interests and concerns in developing knowledge that will reduce the destructive effects of abused drugs on the individual and society. The CPDD is unique in bringing together annually at a single scientific meeting an outstanding group of basic and clinical investigators working in the field of drug dependence. This year, as usual, the monograph presents an excellent collection of papers. It also contains progress reports of the abuse liability testing program funded by NIDA and carried out in conjunction with the CPDD. This program continues to represent an example of a highly successful government/private sector cooperative effort. I am sure that members of the scientific community and other interested readers will find this volume to be a valuable "state-of-the art" summary of the latest research into the biological, behavioral, and chemical bases of drug abuse. Charles R. Schuster, Ph.D. Director National Institute on Drug Abuse iii ACKNOWLEDGMENT The Committee on Problems of Drug Dependence, Inc., an independent, nonprofit organization, conducts drug testing and evaluations for academic institutions, government, and industry. This monograph is based upon papers presented or read by title at the 48th Annual Scientific Meeting of the CPDD, held in Tahoe City, California, on June 16-18, 1986. In the interest of rapid dissemination, it is published in the NIDA Research Monograph series as reviewed and submitted by the CPDD. Dr. Louis S. Harris, the editor of the monograph, is chairman of the Department of Pharmacology, Medical College of Virginia, Richmond. COPYRIGHT STATUS Figures 1 - 7, on pages 21 - 26, are copyrighted by Williams & Wilkins and are reproduced by permission. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder's permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U. S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this publication are used only because they are considered essential in the context of the studies reported herein. DHHS publication number (ADM)87-1508 Printed 1987 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of American Statistics Index, BioSciences Information Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharmacology Abstracts. iv The Committee on Problems of Drug Dependence, Inc. MEMBERS, COMMITTEE ON PROBLEMS OF DRUG DEPENDENCE, INC. Mary Jeanne Kreek, Chairman Theodore J. Cicero, Past Chairman William L. Dewey, Chairman-Elect Martin W. Adler Thomas F. Burks Richard A. Deitrich Loretta P. Finnegan Marian W. Fischman Roland R. Griffiths Leo E. Hollister Donald R. Jasinski Lloyd D. Johnston John Kaplan Conan Kornetsky Horace Loh Akira E. Takemori EXECUTIVE SECRETARY Joseph Cochin (deceased) MEMBERS, BOARD OF DIRECTORS Beny J. Primm, Chairman Natl Medical Assn Joseph V. Brady Soc Behavioral Med Raymond W. Houde Am Soc Clini Pharmacol Ther Keith F. Killam Am Soc Pharmacol Exptl Ther Everette L. May Am Chemical Society Jack H. Mendelson Am Psychiatric Assn E. L. Way Am Coll Neuropsychopharmacol James H. Woods Am Psychological Assn v COMMITTEE CHAIRMEN MEMBERS, PROGRAM COMMITTEE Charles W. Gorodetzky By-Laws Louis S. Harris, Chairman Louis S. Harris Everette L. May Scientific Meetings Joyce H. Pye Arthur E. Jacobson Drug Testing Program MEMBERS, COMMITTEE ON ARRANGEMENTS PERMANENT LIAISON Keith F. Killam Jerome Jaffe Harold Kalant Howard McClain Charles O'Brien Boris Tabakoff Edward C. TOCUS CONTRIBUTING FIRMS, 1985-86 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 Sandoz, Ltd. (Basle) Ayerst, Canada Sandoz, Ltd. Bristol-Meyers Company Schering Corporation Burroughs Welcome Company Searle Research and Chemie Linz AG Development Ciba-Geigy Corporation Sempa, Chemie, S.A. E.I. Du Pont de Nemours Co. Sterling Drugs, Inc. Glaxo Syntex Corporation Hoechst-Roussel Pharmaceuticals Tanabe Seiyaku Company Inc. The Upjohn Company Hoffman-La Roche, Inc. ICI Americas, Inc. Key Pharmaceuticals, Inc. Knoll Pharmaceutical Company Lilly Research Laboratories McNeil Pharmaceuticals Merck, Sharp & Dohme Research Labs Monsanto Company Ortho Pharmaceutical Corporation Parke Davis (Warner-Lambert) H. G. Pars Pharmaceuticals, Inc. Pfizer Central Research Reckitt & Colman Pharmaceutical Div. Revlon A.H. Robins vi Contents Plenary Session In Memoriam: Joseph Cochin, M.D., Ph.D., 1916-1985 Louis S. Harris 1 Presentation of J. Michael Morrison Award William L. Dewey 2 J. Michael Morrison Award, 1986 Edward C. Tocus 4 Introduction of Nathan B. Eddy Award Recipient, 1986 Louis S. Harris 7 Nathan B. Eddy Memorial Award Lecture: Tolerance and its Significance for Drug and Alcohol Dependence Harold Kalant 9 Symposium In Memoriam: Joseph Cochin Mechanisms of Opioid Tolerance and Dependence Early Studies of Tolerance to Morphine Conan Kornetsky 20 Acute and Chronic Tolerance Relevance for Clinical Practice Carl Rosow 29 Recent Studies on Heterogeneity and Isolation of Opioid Receptors Eric J. Simon 35 Role of the Spinal Cord in the Development of Opiate Tolerance and Dependence A. E. Takemori; Gary E. DeLander; and P. S. Portoghese 42 Neural Substrates of Opioid Tolerance and Dependence George F. Koob 46 Tolerance and Dependence: Implications for the Pharmacological Treatment of Addiction Mary Jeanne Kreek 53 Mechanisms of Opioid Tolerance and Dependence: