PSYCHOSTIMULANT REGULATION OF NEURAL GENE EXPRESSION

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Understanding the precise mechanisms by which cocaine produces its effects is a fundamental goal of drug abuse research. Progress has been made in defining the immediate biochemical actions of cocaine as well as its behavioral effects, but much remains to be learned about the mechanisms underlying its clinically relevant actions, especially its reinforcing properties and its production of dependence. It is apparent that cocaine has a very complex pharmacology and that additional methods of study will be needed to fully delineate its mechanism of action. Recently there has been evidence that neural activity and psychotropic drugs can regulate gene expression in the brain with the implication that such mechanisms can mediate long-lasting changes in neuronal functioning. For example, cocaine administration has been shown to activate expression of c-fos, a cellular immediate early gene (IEG) in rat brain. Cellular IEG's have been proposed to function as transcriptional regulators, coupling extracellular signals to changes in expression of target genes that are involved in neural signaling. The goals of the present proposal are to characterize the effects of cocaine on expression of both IEG's and candidate target genes encoding such cell-specific products as neurotransmitters, neurotransmitter receptors, and neural growth factors. Mapping of IEG activation will allow us to define cell groups which are direct or indirect targets of cocaine action. Comparison of cocaine's effects on gene expression with other related compounds may suggest mechanisms of action for cocaine that are relevant to its reinforcing properties. Finally, analysis of IEG expression together with expression of potential target genes will provide information about the cascade of intranuclear events that could lead to long-term alterations in neuronal functioning as a result of cocaine administration. These studies are likely to be a first step in identifying aspects of cocaine-induced neural plasticity which are relevant to behavior and to suggest mechanistic studies of how cocaine induces changes in gene expression at the cellular and molecular levels.