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National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Assessing Neurotoxicity of Drugs of Abuse 136 U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health Assessing Neurotoxicity of Drugs of Abuse Editor: Lynda Erinoff, Ph.D. NIDA Research Monograph 136 1993 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGMENT This monograph is based on the papers and discussions from a technical review on “Assessing Neurotoxicity of Drugs of Abuse” held on May 20-21, 1991, in Bethesda, MD. The technical review was sponsored by the National Institute on Drug Abuse (NIDA). COPYRIGHT STATUS NIDA has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. 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. The chapters by Jensen and colleagues and Boyes were reviewed in accordance with US. Environmental Protection Agency policy and approved for publication: mention of trade names or commercial products in these chapters does not constitute endorsement or recommendation for use. 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.” National Institute on Drug Abuse NIH Publication No. 93-3644 Printed 1993 Contents Page Preface . v Lynda Erinoff Neurobehavioral Methods Used in Neurotoxicology. 1 Hugh A. Tilson Behavioral Consequences of Partial Monoamine Depletion in the CNS After Methamphetamine-Like Drugs: The Conflict Between Pharmacology and Toxicology. 34 Lewis S. Seiden, William L. Woolverton, Stanley A. Lorens, Joseph E.G. Williams, Rebecca L. Corwin, Norio Hata, Mary Olimski Strategies for Detecting Subclinical Monoamine Depletions in Humans . 53 Una D. McCann and George A. Ricaurte Sensory Evoked Potentials: Measures of Neurotoxicity . 63 William K. Boyes Silver Staining as a Tool for Neurotoxic Assessment . 101 Carlos A. Beltramino, José de Olmos, Ferenc Gallyas, Lennart Heimer, and Lászó Záborszky Mapping Toxicant-Induced Nervous System Damage With a Cupric Silver Stain: A Quantitative Analysis of Neural Degeneration Induced by 3,4-Methylenedioxymethamphetamine . 133 Karl F. Jensen, Jeanene Olin, Najwa Haykal-Coates, James O’Callaghan, Diane B. Miller, and José S. de Olmos iii Reactions of 5-HT Neurons to Drugs of Abuse: Neurotoxicity and Plasticity. .155 Mary Ann Wilson, Laura A. Mamounas, Kenneth H. Fasman, Karen J. Axt, and Mark E. Molliver Quantification of Reactive Gliosis as an Approach to Neurotoxicity Assessment. 188 James P. O’Callaghan and Diane B. Miller Pharmacokinetic Approaches to the Study of Drug Action and Toxicity. 213 Arthur K. Cho, Masayuki Hiramatsu, Yoshito Kumagai, and Nita Patel Mechanisms Mediating Biogenic Amine Deficits Induced by Amphetamine and Its Congeners. .226 James W. Gibb, Michel Johnson, Donna M. Stone, and Glen R. Hanson Neurotoxicity and Drugs of Abuse: Cannabinoid Interaction With Brain Glucocorticoid Receptors . .242 Philip W. Landfield and J. Charles Eldridge Nitric Oxide as a Mediator of Neurotoxicity . 253 Ted M. Dawson, Valina L. Dawson, and Solomon H. Snyder List of NIDA Research Monographs . 274 iv Preface This monograph is the result of a technical review meeting that was held May 20-21, 1991. The National Institute on Drug Abuse (NIDA) supports neurotoxicity research as part of its mandate to explore the consequences of drug abuse. This research has provided important data on the neurotoxicity of several abuse substances, such as amphetamine and its congeners; tetrahydrocannabinol, the psychoactive component of marijuana; and phencyclidine. These NIDA-supported studies also have served to further public health on a broader scale by leading to the development of new methodologies for studying neurotoxicity and by elucidating general principles that will guide future research in neurotoxicology. During the course of the technical review meeting, a consensus was reached that no one technique could be used to define a neurotoxic effect but, rather, that confluent data from a variety of tests are needed to establish neurotoxicity. A variety of different methodologies were presented, although by no means all those being employed in the field. In general, the methodologies could be divided into those for screening or hazard identification and those for characterizing neurotoxicity, including studies of mechanism of action. Screens for evaluating large numbers of compounds are of great value to regulatory scientists and are useful in the drug abuse field to evaluate new drugs of abuse. Several presentations focused on screening methodologies based on behavior, neurophysiology, neuroanatomy, or neurochemistry. Other presentations focused on different methodologies designed to study underlying mechanisms of neurotoxicity. A knowledge of the basic mechanisms of neurotoxicity may help researchers understand some of the effects of drugs of abuse and may provide useful models for studying neurodegenerative diseases. At the meeting, Dr. John Olney presented a paper on MK801 neurotoxicity, but time constraints prevented him from writing a chapter for this monograph. To get a sense of the content of Dr. Olney’s talk, I recommend the paper by Olney, J.W.; LaBruyere, J.; Wang, G.; Wozniak, D.F.; Price, M.T.; and Sesma, M.A., “NMDA antagonist neurotoxicity: Mechanism and prevention,” Science, 254, 1515-1518, 1991. In addition to presenting different methodologies, Dr. Olney and colleagues pointed out the importance of understanding the neural circuitry mediating neurotoxic effects. V A number of neurotoxicologists and neuroscientists who did not present papers were active participants in this meeting and contributed to the lively discussion following each talk. Unfortunately, there is no roster of meeting participants, so I cannot thank each person individually. In transcribing the discussion, where possible I have identified the questioner. Several participants were identified by name on the tape, and they are Tom Sobotka, Ph.D., and Nate Appel, Ph.D., of the US. Food and Drug Administration; Diane Miller, Ph.D., of the U.S. Environmental Protection Agency; and Rona Ramsay, Ph.D., of the University of California, San Francisco. I think the discussions were exceedingly valuable, and they have been included following each chapter. Because of taping failure, the discussions following the presentations by Dr. O’Callaghan and Dr. Cho were lost. I hope that the readers of this monograph get some sense of the enthusiasm of the participants and of the spirited discussions that took place on the state of the science. All the authors have provided superb chapters that should stimulate readers to think about the methodological issues raised in this monograph. AUTHOR Lynda Erinoff, Ph.D. Project Officer Neurosciences Research Branch Division of Basic Research National Institute on Drug Abuse Parklawn Building, Room 1DA-31 5600 Fishers Lane Rockville, MD 20857 vi Neurobehavioral Methods Used in Neurotoxicology Hugh A. Tilson INTRODUCTION Neurotoxicity has been defined as any adverse effect on the structure or function of the central and/or peripheral nervous systems produced by a biological, chemical, or physical agent (Tilson 1990a). Historically, toxicity has been defined in anatomical or structural terms (Weiss 1988). It is now generally accepted that neurotoxic effects can be identified and characterized at one of many levels of organization of the nervous system, including the chemical, anatomical, physiological, and neurobehavioral levels. Recently, there has been an increased reliance on neurobehavioral indices of neurotoxicity to detect and characterize neurotoxicity (Weiss and Laties 1975; Zbinden et al. 1983; Annau 1986; Tilson 1987, l990b; Cory-Slechta 1989). It has been suggested that because behavior is the net result of integrated sensory, motor, and cognitive function occurring in the nervous system, chemical- induced changes in behavior may be a relatively sensitive indicator of nervous system dysfunction (National Academy of Sciences 1975). In some cases, the dose-effect curve for neurobehavioral measures may lie to the left of other endpoints of toxicity. As pointed out by Weiss (l988), neurobehavioral assessments are important because it is often the case that one of the earliest indications of exposure to neurotoxicants is subtle behavioral impairment such as paresthesias or short-term memory
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