NIDA Research Monograph Series #125: Activation of Immediate Early Genes by Drugs of Abuse

225 Pages·1993·19.8 MB·English

by  Grzanna,Rreinhard (editor), Brown, Roger M (editor)

National Institute on Drug Abuse
RESEARCH
MONOGRAPH SERIES
Activation of Immediate
Early Genes by Drugs
of Abuse
125
U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health
Activation of Immediate
Early Genes By Drugs of
Abuse
Editors:
Reinhard Grzanna, Ph.D.
Roger M. Brown, Ph.D.
NIDA Research Monograph 125
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 “Activation of Immediate Early Genes by Drugs of Abuse” held on
June 3-4, 1991, in Rockville, MD. The technical review was sponsored by the
National Institute on Drug Abuse (NIDA).
COPYRIGHT STATUS
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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.
NIDA Research Monographs are indexed in the “Index Medicus.” They are
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National Institute on Drug Abuse
NIH Publication No. 93-3504
Printed 1993
ii
Contents
Page
Introduction 1
Reinhard Grzanna and Roger M. Brown
Regulation of Immediate Early Gene Expression 3
Brent H. Cochran
Everything Activates C-fos- How Can It Matter? 25
Steven E. Hyman, Barry E. Kosofsky, Tuong V. Nguyen,
Bruce M. Cohen, and Michael J. Comb
Immediate Early Genes: Their Involvement in Physiological
and Pathological Responses in the Nervous System 39
Michael O. Hayward, Tom Curran, and James I. Morgan
Immediate Early Gene Activation and Long-Term Changes
in Neural Function: A Possible Role in Addiction? 54
Harold A. Robertson
Acute Effects of Psychomotor Stimulant Drugs on Gene
Expression in the Striatum 72
Ann M. Graybiel
Functional Organization of the Striatum: Relevance to Actions
of Psychostimulant Drugs of Abuse 82
Charles R. Gerfen
iii
Regulation of Neural Gene Expression in Opiate and
Cocaine Addiction 92
Eric J. Nestler, Clare M. Bergson. Xavier Guitart,
and Bruce T. Hope
C-Fos and Fos-Related Antigens as Markers for Neuronal
Activity: Perspectives From Neuroendocrine Systems 117
Gloria E. Hoffman, Wen-Sen Lee, M. Susan Smith, Rula Abbud,
Michelle M. Roberts, Alan G. Robinson, and Joseph G. Verbalis
Mechanisms of Opioid-Mediated Antinociception: Correlation
of Fos Expression and Behavior 134
Kathleen R. Gogas, Jon D. Levine, and Allan I. Basbaum
The Ontogeny of Immediate Early Gene Response to Cocaine:
A Molecular Analysis of the Effects of Cocaine on Developing
Rat Brain 181
Barry E. Kosofsky and Steven E. Hyman
NMDA Receptor Blockade Prevents Translation, but Not Transcription,
of the C-fos Gene Following Stimulation With Multiple Extracellular
Signals in Cultured Cortical Neurons: Implications for Plasticity and
Molecular Memory 172
Frank R. Sharp, Kinya Hisanaga, and Stephen M. Sagar
Induction and Suppression of Proto-Oncogenes in Rat
Striatum After Single or Multiple Treatments With Cocaine
or GBR-12909 181
Michael J. ladaroia, Eric J. Chuang, Choh-Lun Yeung, Yin Hoo,
Mayme Silverthorn, Jun Gu, and Gaetano Draisci
List of NIDA Research Monographs 212
iv
Introduction
Reinhard Grzanna and Roger M. Brown
A major goal in drug abuse research is to determine the neurobiological
mechanisms by which drugs of abuse produce tolerance, dependence,
and addiction. These behavioral manifestations of drug abuse have been
attributed to longlasting neuroadaptations in central nervous system (CNS)
neurons. The nature and extent of these neuroadaptations remain to be
characterized, but investigators agree that they are the result of drug-induced
alterations in neuronal gene expression.
The recent discovery that cocaine and amphetamine rapidly and transiently
induce immediate early genes (IEGs) provided the most direct indication
that drugs of abuse can profoundly influence gene expression. Following
their description a few years ago, IEGs and their protein products became
recognized as important links by which extracellular signals can produce
alterations in gene transcription. Turning on IEG expression by drugs of
abuse may be the initial step by which drugs alter the expression of late
genes to produce longlasting changes in neuronal functions. Thus, studies
of the effects of drugs of abuse on IEGs may hold the key to providing the
answer to how drugs of abuse produce long-term changes in neurons.
Studies of this class of genes also should provide a powerful approach to
explore correlations between drug-induced changes in behavior and the
neuronal systems in which drugs permanently alter gene expression.
Studies of the effects of drugs of abuse on IEGs are greatly facilitated by the
availability of methods to visualize the activity states of these genes in tissue
sections by immunohistochemistry and by in situ hybridization histochemistry.
This has opened a new and promising approach to define drug-induced,
permanent changes in the CNS and to identify the neuronal circuitries in
which they occur.
The chapters in this volume were presented at a conference on June 3-4, 1991,
in Rockville, MD, organized by the National Institute on Drug Abuse. The main
goal of this conference was to assess the potential impact of studies of IEGs in
the field of drug abuse research. The contributors to this volume reviewed
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current developments in the field and discussed to what extent
studies of the effects of drugs of abuse on IEGs are likely to provide new
insights into the molecular underpinning of drug-seeking behavior.
Among the topics discussed were the specificity of the activation of IEGs
by drugs of abuse, the nature of the long-term alterations following the
induction, and the possible relationship between the observed changes in
IEG activity and behavior. Many of the questions discussed remain unresolved.
Yet, there was excitement about the remarkable specificity in the patterns of
IEG activation induced by different drugs in the CNS. The participants
expressed confidence about the prospects of linking drug-induced IEG
induction to specific alterations in peptide gene expression in identified
populations of CNS neurons.
This volume reflects the considerable optimism among drug abuse researchers
that studies of IEGs offer a new path to identify the long-term effects of drug
exposure in the CNS. The chapters reveal a sense of confidence that studies
of the action of drugs of abuse on IEGs will greatly facilitate efforts to identify
the neuronal systems critically involved in the development of drug addiction
and the nature of the changes produced within these systems.
AUTHORS
Reinhard Grzanna, Ph.D.
Senior Staff Fellow
Roger M. Brown, Ph.D.
Chief
Neuroscience Research Branch
National Institute on Drug Abuse
Parklawn Building, Room 11A-33
5600 Fishers Lane
Rockville, MD 20657
2
Regulation of Immediate Early Gene
Expression
Brent H. Cochran
INTRODUCTION
Recently, much excitement has been generated by the finding that various
immediate early genes (IEGs) are expressed in neurons in response to a
variety of neurotropic stimuli. Part of the reason these findings have generated
so much interest is that earlier work has suggested that long-term changes in
nervous system behavior require changes in gene expression (Goelet et al.
1986). Thus, since changes in IEG expression are coupled to neuronal activity
and neurotransmitter release, it may now be possible, using in situ techniques
that provide resolution at the single-cell level, to correlate the physiological state
of a neuron with behavioral and physiological outputs. This chapter reviews
what is currently known about IEGs and speculates on what roles these genes
might be playing in the operation of the nervous system.
IEGs (sometimes called early-response genes or primary-response genes)
were first identified not in the nervous system but through the study of cell
growth regulation. During the 1970s it became apparent that polypeptide
growth factors were key modulators of cell growth and differentiation of
multicellular organisms. Early studies had suggested that the mitogenic effects
of serum growth factors were mediated in part by the ability of these factors to
regulate gene expression (Smith and Stiles 1981). To identify such genes,
several investigators set out to clone them by differential or subtractive cDNA
cloning. The first of such genes cloned were those induced by the platelet-
derived growth factor (PDGF) in 3T3 fibroblasts (Cochran et al. 1983). The
genes cloned in this study displayed regulatory properties that are characteristic
of most early-response genes now known. These genes are induced rapidly
within 1 hour of growth factor treatment and are regulated at the level of
transcription (Cochran et al. 1988). They are induced by polypeptide growth
factors that bind to cell surface receptors in the absence of new protein
synthesis. Therefore, the induction of these genes is a primary response to
events at the cell surface and not secondary to other waves of gene expression
or changes in growth state of the cell. The ability of early-response genes to be
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induced in the absence of new protein synthesis distinguishes this set of genes
from other genes, which may be called late-response genes (those that are
expressed only if protein synthesis is allowed). Late-response genes are likely
to be targets of transcription factors induced in the early part of the response.
Subsequently, it was found that some of the IEGs are the cellular homologs
of various retroviral oncogenes, including those for c-myc, c-fos, and c-jun
(Cochran et al. 1984; Greenberg and Ziff 1984; Kelly et al, 1983; Lamph et al.
1988; Muller et al. 1984; Ryder and Nathans 1988). Studies using antisense
RNAs or oligonucleotides or antibodies have shown that the expression of c-fos
and proto-oncogenes is necessary for the entry of quiescent fibroblasts into the
cell cycle (Heikkila et al. 1987; Holt et al. 1988, 1988; Nishikura and Murray
1987; Wickstrom et al. 1988). Microinjection or overexpression of c-myc by
itself can potentiate the response of fibroblasts to other growth factors (Armelin
et al. 1984; Kaczmarek et al. 1985). However, the finding that some IEGs can
also be induced in cells such as neurons that have terminally differentiated
indicates that the IEGs may have roles to play in processes other than cell
growth regulation (Bravo et al. 1985; Curran and Morgan 1985; Greenberg
et al. 1985; Kruijer et al. 1985).
A wide variety of early-response genes have been identified from studies of
serum growth factor-stimulated fibroblasts (Almendral et al. 1988; Cochran et al.
1983; Lau and Nathans 1985, 1987; Lim et al. 1987). The total number of such
genes is unclear but is probably in the range of 50 to 100. It can be seen from
table 1, which lists some of these genes, that there are a wide variety of gene
products encoded by early-response genes. The two best characterized
classes of such genes are transcription factor genes and secreted gene
products. However, these are not the only type of gene products represented.
Others such as ß-actin and rho-B encode cytoskeletal and signal transduction
molecules, respectively (Greenberg and Ziff 1984; Jahner and Hunter 1991 a).
The best characterized of these genes are transcription factors, which can be
subdivided into several distinct categories. C-Fos and c-Jun are DNA-binding
proteins that form heterodimers via their leucine zipper domains (Bohmann et
al. 1987; Chiu et al. 1988; Landschulz et al. 1988; O’Shea et al. 1989; Rauscher
et al. 1988a, 1988b; Vinson et al. 1989). Each of these genes has several
related homologs (i.e., jun-B, jun-D, fra-1, and fos-B), which all can form
heterodimers with opposite members of the family (Hai and Curran 1991;
Halazonetis et al. 1988; Nakabeppu et al. 1988). In addition, c-jun can form a
homodimer. Thus, the number of dimeric complexes formed in the cells by this
family of gene products is larger than the number of genes that encode them.
Almost all these homodimeric and heterodimeric complexes can bind to the
activator protein-1 (AP-1) consensus site (TGACTCA), although the affinity of
a given complex for a given site can vary (Hai and Curran 1991; Kovary and
Bravo 1991; Ryseck and Bravo 1991). Different fos/jun complexes have
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TABLE 1. A list of representative early-response genes*
Gene Possible Function References
C-myc Transcriptional modulator? Kelly et al. 1983; Murre et al. 1989
Helix loop helix
JE Cytokine Cochran et al. 1983; Rollins et al.
1988
KC, MGSA, gro Cytokine Anisowicz et al. 1987; Cochran et al.
1983; Richmond et al. 1988
C-fos Transcription factor Cochran et al. 1984; Greenberg and
Leucine zipper Ziff 1984; Kruijer et al. 1984; Muller
et al. 1984
Fra-1 Transcription factor Cohen and Curren 1988
Leucine zipper
Fos-B Transcription factor Zerial et al. 1989
Leucine zipper
Zif/268, egr-1 , Transcription factor Christy et al. 1988; Lemaire et al.
TIS8, KROX24, Zinc finger 1988; Milbrandt 1987; Sukhatme
NGFIA et al. 1988
KROX20, egr-2 Transcription factor Chavrier et al. 1989
Zinc finger
NGFIB, TlS1, Steroid receptor Hazel et al. 1988; Milbrandt 1988
nur77 Superfamily
C-jun Transcription factor Lamph et al. 1988; Ryder and
Leucine zipper Nathans 1988
Jun-B Transcription factor Ryder et al. 1988
Leucine zipper
ß-actin Cytoskeletal component Greenberg and Ziff 1984
SRF Transcription factor Norman et al. 1988
2’-5’ oligo- Enzyme Garcia-Blanco et al. 1989
adenylate
synthetase
Rho-B Ras-like G protein Jahner and Hunter 1991 a
*For a more comprehensive list, see Herschman (1991).
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