National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Neurobiological Approaches to Brain-Behavior Interaction U.S. Department of Health and Human Services1 • Public2 Health Service4 • National Institutes of Health Neurobiological Approaches to Brain-Behavior Interaction Editors: Joseph Frascella, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Roger M. Brown, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Research Monograph 124 1992 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 ACKNOWLEDGMENT This monograph is based on the papers and discussion from a technical review on “Neurobiological Approaches to Brain-Behavior Interaction,” held on September 5-6, 1990, in Bethesda, MD. The review meeting was sponsored by the 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 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 US. 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. NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of American Statistics Index, BioSciences lnformation Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharmacology Abstracts. DHHS publication number (ADM)92-1846 Printed 1992 ii Contents Preface v Microdialysis in the Study of Psychostimulants and the Neural Substrate for Reinforcement: Focus on Dopamine and Serotonin 1 Bartley G. Hoebel, Luis Hernandez, Gregory P. Mark, and Emmanuel Pothos Neurophysiological Approaches to Receptor Pharmacodynamics 35 Francis J. White Psychomotor Stimulant Effects on Single Neurons in Awake, Behaving Rats 57 Mark O. West, Laura L. Peoples, Martin Wolske, and Sfeven I. Dworkin Brain-Stimulation Reward: A Model for the Study of the Rewarding Effects of Abused Drugs 73 Conan Kornefsky and George Bain New Neuroimaging Techniques for Investigating Brain-Behavior Relationships 95 William J. Jagusf and Thomas F. Budinger iii Studying Psychoactive Drugs With Positron Emission Tomography: Relationships Between Mood and Metabolic Rate 117 Harriet de Wit, John Metz, and Malcolm Cooper Metabolic Mapping Methods for Identifying the Neural Substrates of the Effects of Abused Substances 135 Linda J. Porrino Interactions of Neurotransmitters With Drugs and Behavior 153 Lewis S. Seiden Historical Influences Affecting the Behavioral Actions of Abused Drugs 161 James E. Barrett Importance of Behavioral Controls in the Analysis of Ongoing Events 173 Steven I. Dworkin, Linda J. Porrino, and James E. Smith Cocaine Self-Administration: Pharmacology and Behavior 189 William L. Woolvelton Multivariate and Nonlinear Approaches to Characterizing Drug Effects on the Locomotor and Investigatory Behavior of Rats 203 Mark A. Geyer and Martin P. Paulus Neurobiological Approaches to Brain-Behavior Interaction: Summary and Overview 237 George F. Koob iv Preface Neurobiological Approaches to Brain-Behavior Interaction is the result of a NIDA-sponsored technical review meeting held September 5-6, 1989, in Bethesda, MD. (For an overview of the presentations see “Neurobiological Approaches to Brain-Behavior Interaction: Summary and Overview.“) Neuroscientists and behavioral scientists were brought together to share ideas and techniques for studying brain mechanisms that underlie or modify behavior. Technically, we have come a long way from the early 1960s when large inferential leaps were necessary to describe a behavior or function with respect to neurophysiological, neuropharmacological, and neurochemical events. With this approach it was necessary, for example, to run drug dose-response or time-response evaluations on a behaving group of animals in parallel with a different set of animals that was used for neurochemical determinations; less precise and specific methods were used to determine whole-brain monoamine levels and metabolite data to explain synaptic events as well as to provide a basis for drawing correlations with behavioral effects of a drug. Recently, however, advances in technology and methodological developments have been made that allow for direct correlations between brain changes and behavioral events. Direct measurement of synaptic events occurring in discrete brain regions now can be assessed during ongoing behavior. This capability has the potential for immensely magnifying our understanding of relationships between brain structure and function tremendously enhances our capacity for dealing with malfunctions at the cellular level, especially with respect to understanding the direct effects of drugs of abuse on the central nervous system (CNS), and further, to reveal how these drug-CNS interactions alter behavior. The purpose of this technical review was twofold. First, an important aim was to examine the various techniques for monitoring neural activity, synaptic events, and biochemical interactions during ongoing behavior by discussing the strengths and weaknesses of the current methodologies. Toward this end, discussions are provided in this monograph on the 2-deoxyglucose technique (“Importance of Behavioral Controls in the Analysis of Ongoing Events); in vivo v voltammetry and microdialysis (“Microdialysis in the Study of Psychostimulants and the Neural Substrate for Reinforcement: Focus on Dopamine and Serotonin”); computer imaging techniques such as positron emission tomography, single-photon emission computed tomography, and magnetic resonance tomography (“Studying Psychoactive Drugs With Positron Emission Tomography: Relationships Between Mood and Metabolic Rate” and “New Neuroimaging Techniques for Investigating Brain-Behavior Relationships”); and neurophysiological recording methods (“Neurophysiological Approaches to Receptor Pharmacodynamics” and “Psychomotor Stimulant Effects on Single Neurons in Awake, Behaving Rats”). As we enter the Decade of the Brain, information is becoming available concerning the complex response of the brain to drugs of abuse as well as the underlying events that unfold during the development of addiction. Drug addiction begins with a relatively simple neuropharmacological action of a drug acting at a specific site. A resultant cascade of neural and chemical events takes place to produce an experience, which is usually positive. This positive experience is highly reinforcing and often leads to the compulsive behavior and abuse of the drug despite its damaging consequences. With repeated drug exposure, brain mechanisms most likely change or adapt to the presence of the drug, often resulting in an alteration in the ability to process information. Because drug addiction is a behavioral phenomenon resulting from a modification of neural function, the role of the behavioral sciences in understanding drug abuse is absolutely essential. The Neuroscience Research Branch of the National Institute on Drug Abuse strongly encourages interaction between the neurobiological sciences and the behavioral sciences. Consequently, the second purpose of this technical review was to emphasize the equally important perspective that behavioral events influence the brain and, thus, the drug-brain-behavior interaction is an important consideration in evaluating neuropharmacological data. Neurobiologists should be aware that a behavioral action of a psychotropic drug depends on many factors, of which the interaction between a drug and its corresponding receptor or receptors is only one. The modification of behavior is the final common pathway of a drug’s action at a synapse whose influence might lie on a continuum from being very critical to being far removed from other circuits that determine behavior. Consequently, the ultimate effect of a drug on behavior might be modified by changes in activity within the brain’s complex circuitry. These changes might come from environmental or situational factors that affect neural events, such as previous history, environmental vi stimuli, and situation (“Importance of Behavioral Controls in the Analysis of Ongoing Events”). Locomotor activity is sometimes thought to be a simple drug screen, yet even this seemingly simple behavior is made up of complex components (“Multivariate and Nonlinear Approaches to Charcterizing Drug Effects on the Locomotor and Investigatory Behavior of Rats”). The use of behavior to study the neural basis of drug action is a powerful tool (“Brain-Stimulation Reward: A Model for the Study of the Rewarding Effects of Abused Drugs” and “Cocaine Self-Administration: Pharmacology