PHARMACOLOGICAL REGULATION 4 GENE EXPRESSION in feCNS Pharmacology and Toxicology: Basic and Clinical Aspects Mannfred A. Hollinger, Series Editor University of California, Davis Forthcoming Titles Antibody Therapeutics, William J. Harris and John R. Adair Anabolic Treatment for Osteoporosis, James F. Whitfield and Paul Morley Antisense Oligodeonucleotides as Novel Pharmacological Therapeutic Agents, Benjamin Weiss Basis to Toxicity Testing, Second Edition, Donald J. Ecobichon CNS Injuries: Cellular Responses and Pharmacological Strategies, Martin Berry and Ann Logan Lead and Public Health: Integrated Risk Assessment, Paul Mushak Molecular Bases of Anesthesia, Eric Moody and Phil Skolnick Muscarinic Receptor Subtypes in Smooth Muscle, Richard M. Eglen Receptor Characterization and Regulation, Devendra K. Agrawal Published Titles Inflammatory Cells and Mediators in Bronchial Asthma, 1990, Devendra K. Agrawal and Robert G. 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Kimball Chemoattractant Ligands and Their Receptors, 1996, Richard Horuk Pharmacological Regulation of Gene Expression in the CNS, 1996, Kalpana Merchant PHARMACOLOGICAL REGULATION of GENE EXPRESSION in ifeCNS Edited by Kalpana Merchant, Ph.D. CNS Diseases Research Pharmacia & Upjohn, Inc. , Kalamazoo Michigan First published 1996 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 Reissued 2018 by CRC Press © 1996 by Taylor & Francis CRC Press is an imprint of Taylor & Francis Group, an Infonna business No claim to original U.S. Government works This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. 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ISBN 13: 978-1-138-10574-4 (hbk) ISBN 13: 978-0-203-71114-9 (ebk) Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Acquiring Editor: Paul Petralia Cover design: Dawn Boyd PrePress: Carlos Esser P reface Extracellular environmental signals received by neurons first pro­ duce an activation of second messenger systems associated with cell surface receptors. This kind of an immediate biological response is often short-lived, governed primarily by temporal patterns of protein phosphorylation/dephosphorylation events. However, it can lead rap­ idly to specific short- and long-term changes in gene expression which, in some cases, may permanently alter the phenotype of a neuron. Steroid hormone receptors can bypass the second messenger systems and directly lead to genomic responses. The phenotypic alterations in the neurons determine the outcome of subsequent homologous and heterologous cell surface stimuli. This phenomenon, termed neuronal plasticity, plays a critical role in physiological as well as pathological effects in the central nervous system. Learning and memory is a prime example of a physiological process that involves genomic responses. On the other hand, stress-induced alterations in neuronal phenotype may underlie the pathophysiology of diseases such as schizophrenia and depression. It would be obvious then that phenotypic adaptations by neurons to pharmacological agents play a pivotal role not only in dictating the immediate response but also in such phenomena as drug tolerance and sensitization thought to underlie dependence and addic­ tion liability. The importance of neuronal plasticity in pharmacological regula­ tion of neuronal activity cannot be exemplified better than that dem­ onstrated by studies of dopamine-mediated gene regulation in the neostriatum. The neostriatum is a neurochemically rich structure re­ ceiving converging neural inputs from a number of distant sites asso­ ciated with the basal ganglia. The integration of various neural signals within the neostriatum regulates such complex behaviors as emotions, motivation, addiction as well as movement, and dopaminergic neu­ rotransmission plays a key role in this process. Alterations in dopamine neurotransmission are implicated in the pathophysiology and pharma­ cotherapy of psychotic disorders (such as schizophrenia) and move­ ment disorder (e.g., Parkinson's disease), as well as addiction to psy­ chostimulants such as cocaine and amphetamine. The efficacy of, as well as clinical complications produced by, long-term dopaminergic therapy of these diseases involves adaptive alterations in targeted neu­ rons. Additionally, the addiction liability of psychostimulants is thought to be due to phenotypic alterations induced by endogenously released dopamine. Hence, an understanding of the influence of dopamine in acute and long-term changes in gene expression within the neostriatum is crucial for gaining insight into cellular mechanisms involved in integration of divergent stimuli within the striatum and in phenomena involved in neuronal adaptations. This in turn will shed light on the pathophysiology of central disorders involving the basal ganglia and offer fundamentally novel approaches for the treatment of these diseases. This volume is planned to provide a comprehensive overview of dopamine-mediated regulation of gene expression within the striatum and associated regions. The contributors have reviewed a range of studies discussing the interactions of major dopamine receptor families in regulating acute and chronic gene expression within the intrinsic, afferent, and efferent striatal neurons. Additionally, in view of the now established heterogeneity of dopamine receptor subtypes within the major families, a potential role of each receptor subtype in mediating phenotypic and behavioral effects is discussed. The results were de­ rived from the effects of subtype-specific agents as well as the approach of selective knock-down of specific receptors with antisense oligonu­ cleotides. Studies of coordinated expression of transcription regulatory factors, neuropeptide genes as well as genes involved in the synthesis of classical neurotransmitters provide an insight into the complexity of dynamic interactions between transmitter systems within the neostri­ atum. These articles also provide proof that pharmacological alteration in gene expression is an effective method to understand neurotrans­ mitter interactions, both at the level of neural systems and cellular level. Finally, the correlation between drug-induced, long-term phenotypic changes with behavioral effects and the utility of this approach for predicting clinical outcome is exemplified in chronic studies of antip­ sychotic and antiparkinsonian agents. I would like to acknowledge my sincere gratitude to all the con­ tributors of this monograph for sharing my enthusiasm for this volume and making time from their extremely busy schedules for careful prep­ aration of each chapter. Most of all, I am indebted to my husband, Mahesh, for his unending encouragement, constructive criticism, and tolerance of my labors. I would not have taken on this daunting task without his support and so to him I dedicate this book with affection. Kalpana M. Merchant T E he ditor Kalpana M. Merchant, Ph.D., is a Research Scientist in the CNS Diseases Research at the Pharmacia & Upjohn, Inc., in Kalamazoo, Michigan. Dr. Merchant received her B.S. in Pharmacy from Bombay Univer­ sity (India) in 1979. After obtaining research experience at multinational pharmaceutical companies in India for 5 years, she joined the Depart­ ment of Pharmacology and Toxicology at the University of Utah and obtained her Ph.D. in 1989. She did a postdoctoral fellowship in the Department of Pharmacology at the University of Washington in Seattle for 2 years after which she was appointed first as an Acting Assistant Professor and then as Assistant Professor in the Department of Psychi­ atry at the University of Washington, Seattle, in 1991. In 1993 she joined The Upjohn Company as a Research Scientist with an Adjunct appoint­ ment in the Department of Biological Sciences at Western Michigan University. Dr. Merchant is a member of the Society for Neuroscience, the American Association for the Advancement of Sciences, International Neuropeptide Society, and Indian Pharmaceutical Association. She received several undergraduate and graduate scholarships and has been a recipient of the Young Investigator Award from the Inter­ national Schizophrenia Research program. Dr. Merchant received re­ search grants from the Washington Institute for Mental Health Research and Training, The Scottish Rite Schizophrenia Foundation, The Stanley Research Foundation and The National Institute for Neurological Dis­ orders and Stroke. Her current major research interests include molec­ ular mechanisms underlying the pathophysiology and pharmacother­ apy of diseases involving central dopamine systems. Specifically, she studies the involvement of transcription factors and their downstream genetic targets in the pharmacological effects of psychoactive drugs and in animal models of diseases like schizophrenia and Parkinson's disease.