Mechanisms of Cocaine Abuse and Toxicity U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration I Mechanisms of Cocaine Abuse and Toxicity Editors: Doris Clouet, Ph.D. Khursheed Asghar, Ph.D. Roger Brown, Ph.D. Division of Preclinical Research National Institute on Drug Abuse NIDA Research Monograph 88 1988 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, DC 20402 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. MARY L. JACOBSON Temple University School of Medicine National Federation of Parents for Philadelphia,Pennsylvania Drug-Free Youth Omaha, Nebraska SYDNEY ARCHER, Ph.D. Rensselaer Polytechnic lnstitute Troy, New York REESE T. JONES, M.D. Langley Porter Neuropsychiatric lnstitute RICHARD E. BELLEVILLE, Ph.D. San Francisco, California NB Associates, Health Sciences RockviIle, Maryland DENISE KANDEL, Ph.D. KARST J. BESTEMAN College of Physicians and Surgeons of Alcohol and Drug Problems Association Columbia University of North America New York, New York Washington, D.C. GILBERT J. BOTVIN, Ph.D. Cornell Unvirsity Medical College HERBERT KLEBER, M.D. New York, New York Yale University School of Medicine New Haven, Connecticut JOSEPH V. BRADY, Ph.D. The Johns Hopkins University School of Medicine RICHARD RUSSO Baltimore, Maryland New Jersey State Department of Health Trenton, New Jersey THEODORE J. CICERO, Ph.D Washington University School of Medicine St Louis, Missouri NIDA Research Monograph Series CHARLES R. SCHUSTER, Ph.D. Director, NIDA THEODORE M. PINKERT, M.D.. J.D. Acting Associate Director for Science, NIDA Parklawn Buildlng, 5600 Fishers Lane, RockviIle, Maryland 20857 Mechanisms of Cocaine Abuse and Toxicity ACKNOWLEDGMENT This monograph is based upon papers and discussion from a technical review on mechanisms of cocaine abuse and toxicity that took place on September 21-23, 1987, at Rockville, MD. The review meeting was sponsored by the Office of Science and the Division of Preclinical Research, National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copy- righted 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 commer- cial product or company. Trade, proprietary, or company names appearing in this publication are used only because they are con- sidered essential in the context of the studies reported herein. DHHS publication number (ADM)89-1585 Printed 1988, Reprinted 1989 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 Con- tents, Psychological Abstracts, and Psychopharmacology Abstracts. iv Contents Page Foreword ix Pharmacological Effects of Cocaine Relevant to Its Abuse Robert L. Balster 1 Cocaine Receptors on Dopamine Transporters Mediate Cocaine-Reinforced Behavior Michael J. Kuhar, Mary C. Ritz, and John Sharkey 14 Cocaine Receptors on Monoamine Transporters and Sodium Channels Maarten EA. Reith 23 Modulation of Cocaine Receptors lngeborg Hanbauer 44 Sensitization to Cocaine in the Nigrostriatal Dopamine System Nancy R. Zahniser, Joanna Peris, Linda P. Dwoskin, Pamela Curella, Robert P. Yasuda, Laurie O’Keefe, and Sally J. Boyson 55 The Interaction of Cocaine With Central Serotonergic Neuronal Systems: Cellular Electrophysiologic Approaches Joan M. Lakoski and Kathryn A. Cunningham 78 v Page The Effects of Cocaine on Local Cerebral Metabolic Activity Linda J. Porrino and Conan Kornetsky 92 Behavioral Studies of the Reinforcing Properties of Cocaine Chris E. Johanson 107 Pharmacological Modifications of Cocaine and Opioid Self-Administration Gail Winger 125 Reinforcement Pathways for Cocaine George F. Koob and Carol B. Hubner 137 Multiple Dopamine Receptors and the Behavioral Effects of Cocaine W.L. Woolverton and M.S. Kleven 160 Neurobehavioral Pharmacology of Cocaine Steven I. Dworkin and James E. Smith 185 Intracranial Cocaine Self-Administration Nick E. Goeders 199 Psychomotor Stimulant vs. Local Anesthetic Effects of Cocaine: Role of Behavioral Sensitization and Kindling Robert M. Post and Susan R.B. Weiss 217 Genetic Differences in Responses to Cocaine Frank R. George and Steven R. Goldberg 239 Hepatotoxicity of Cocaine Louis Shuster, Christine A. Garhart, James Powers, Yona Grunfeld, and Gary Kanel 250 Lack of Toxic Effects of Cocaine on Dopamine or Serotonin Neurons in the Rat Brain Lewis S. Seiden and Mark S. Kleven 276 vi Page Developmental Effects of Cocaine Diana L. Dow-Edwards 290 Cardiovascular Toxicity of Cocaine R. Douglas Wilkerson 304 Arteriosclerotic Toxicity of Cocaine Ronald O. Langner, Collette L. Bement, and Lynda E. Perry 325 Mechanisms of Cocaine Abuse and Toxicity: An Overview Thomas K. Dunwiddie 337 List of NIDA Research Monographs 354 vii Preface The seriousness of cocaine use is illustrated by population statistics on this drug. The most recent National Household Survey on Drug Abuse1 shows that, in 1985, an estimated 22 million persons in the continental United States had at least tried cocaine. Of these, approximately 12 million individuals used it within the past year and 6 million at least once in the month prior to the survey (prior month use is considered an indication of current use). “Freebasing” has become a common occurrence and is more dangerous than snorting because of the increased pharmacological effects of the drug and the resulting drug craving. The propensity toward freebasing increases with the frequency of use. Seven percent of the population that reported using cocaine only one or two times reported smoking it, whereas 57 percent of those who reported using it 100 times or more had freebased. The popularity of the drug is underscored by figures on teenage use.2 Over half (57 percent) of the graduating high school class of 1987 had tried illicit drugs at least once; 15.2 percent used cocaine, and crack use is estimated as 1 out of every 18 seniors (5.6 percent).2 Although progress is being made through biobehavioral research, a full understanding of the compulsion to keep using cocaine is, as yet, not available. Cocaine produces a number of physiological effects, including psychomotor stimulation, hypertension, tachycardia, anorexia, pupillary dilation, and euphoria. These effects have been related to the two major actions of cocaine: local anesthesia and actions in the central nervous system. Such general pharmacological knowledge, although necessary for further studies, does not provide an under- standing of the basic mechanisms underlying cocaine reinforcement and its abuse. A technical review meeting on “Mechanisms of Cocaine Abuse and Toxicity,” held September 21 to 23,1987, in Rockville, MD, addressed ix the main problems encountered in treating cocaine abusers, which are twofold: to reverse or treat toxic effects of drug overdose and to develop methods of dealing with the drug craving that leads to cocaine abuse. Both of these problems have been examined in their basic biomedical aspects in this review. In particular, the review contains state-of-the-art knowledge of factors that influence drug- seeking behavior in laboratory animals, including drug vulnerability, basic neurochemical mechanisms, and neuronal sites of the “reward” pathway, as well as toxicology, perinatal consequences, and cardio- vascular actions. The proceedings of this conference are presented in the following chapters, concluding with a review of the research described in the conference and, especially, areas where future efforts will be both feasible and productive. The Editors FOOTNOTES 1. National Household Survey on Drug Abuse: Population Estimates 7985. DHHS Pub. No. (ADM) 87-1539. Rockville, MD: National Institute on Drug Abuse, 1987. 79 pp. 2. Johnston, LD.; O’Malley, P.M.; and Bachman, J.G. Illicit Drug Use, Smoking, and Drinking by America’s High School Students, College Students, and Young Adults, 1975-1987. Rockville, MD: National Institute on Drug Abuse, in preparation. x Pharmacological Effects of Cocaine Relevant to Its Abuse Robert L. Balster lNTRODUCTlON The purpose of this paper is to provide