Drugs of abuse and immediate-early genes in the forebrain

Abstract

A diverse array of chemical agents have been self administered by humans to alter the psychological state. Such drugs of abuse include both stimulants and depressants of the central nervous system. However, some commonalties must underlie the neurobiological actions of these drugs, since the desire to take the drugs often crosses from one drug to another. Studies have emphasized a role of the ventral striatum, especially the nucleus accumbens, in the actions of all drugs of abuse, although more recent studies have implicated larger regions of the forebrain. Induction of immediate-early genes has been studied extensively as a marker for activation of neurons in the central nervous system. In this review, we survey the literature reporting activation of immediate-early gene expression in the forebrain, in response to administration of drugs of abuse. All drugs of abuse activate immediate-early gene expression in the striatum, although each drug induces a particular neuroanatomical signature of activation. Most drugs of abuse activate immediate-early gene expression in several additional forebrain regions, including portions of the extended amygdala, cerebral cortex, lateral septum, and midline/intralaminar thalamic nuclei, although regional variations are found depending on the particular drug administered. Common neuropharmacological mechanisms responsible for activation of immediate-early gene expression in the forebrain involve dopaminergic and glutamatergic systems. Speculations on the biological significance and clinical relevance of immediate-early gene expression in response to drugs of abuse are presented.

Morphine-Induced c-fos mRNA Expression in Striatofugal Circuits: Modulation by Dose, Environmental Context, and Drug History

“…The general pattern of immediate early gene (IEG) expression elicited by morphine in the present study (eg, c-fos induction primarily in the most dorsomedial portion of the CPu and cingulate cortex) is consistent with the existing literature (Liu et al, 1994;Garcia et al, 1995;Curran et al, 1996;Erdtmann-Vourliotis et al, 1999b;Frankel et al, 1999b; see Harlan and Garcia (1998) for review). Our results are also consistent with a recent report showing that morphine administration in a stressful environment induces greater c-fos expression in the dorsomedial CPu than morphine administration in a calm environment (Mayer et al, 2002).…”

Augmented D1 Dopamine Receptor Signaling and Immediate-Early Gene Induction in Adult Striatum After Prenatal Cocaine

“…Of special interest are genes encoding proteins that regulate neuronal plasticity including transcription factors (immediate-early genes, IEGs) such as c-fos and zif 268 (28), and synaptic plasticity factors such as Homer proteins (29,30). The striatum is among the brain regions that show the most pronounced changes in gene expression following psychostimulant treatments (31,32). The striatum is part of anatomically distinct cortico-basal ganglia-cortical circuits that mediate planning and execution of motor functions and goal-directed behaviors (33)(34)(35)(36).…”

Motor-Skill Learning-Associated Gene Regulation in the Striatum: Effects of Cocaine

“…These neuronal changes include alterations in gene regulation which are especially pronounced in projection neurons of the striatum (Hyman and Nestler, 1996;Harlan and Garcia, 1998;Torres and Horowitz, 1999;Berke and Hyman, 2000). These neurons are part of cortico-basal ganglia-cortical circuits (Alexander et al, 1986(Alexander et al, , 1990Albin et al, 1989;Groenewegen et al, 1990).…”

“…However, the most profound changes in gene expression induced by a range of addictive drugs are found in dorsal regions of the striatum (Steiner and Gerfen, 1993;Harlan and Garcia, 1998;Berke and Hyman, 2000). Little is known regarding the functional consequences of these neuronal changes.…”