Mechanisms underlying the long-term effects of cocaine on brain function, as well as its extraordinary addictive potential, remain poorly understood. Some insight into the mechanisms of cocaine action have been obtained over the past decade through the identification of specific areas of the brain, termed brain reward regions [e.g., the ventral tegmental area (VTA) and nucleus accumbens (NAc)], as mediators of the reinforcing effects of cocaine and other abused substances. These studies have focused on cocaine regulation of neurotransmitter and receptor systems in these brain regions. The major objective of the proposed studies is to extend these findings by looking beyond the neurotransmitter and receptor levels for additional, post-receptor targets of cocaine action. It is now known that most types of neurotransmitters produce many of their physiological responses in target neurons, including the regulation of gene expression, through a complex cascade of intracellular messengers consisting of G-proteins, second messengers, and protein phosphorylation. The proposed studies will focus on adaptations that develop specifically in these intracellular messenger pathways in brain reward regions to obtain a better understanding of cocaine action. In preliminary investigations, we have shown that chronic administration of cocaine produces alterations in intracellular messengers specifically in brain reward regions. Chronic cocaine decreases levels of Gi-alpha and Go-alpha in the VTA and NAc, and increases levels of adenylate cyclase and cyclic AMP-dependent protein kinase in the NAc, but not in other brain regions studied. These intracellular adaptations could account for some of the known electrophysiological actions of chronic cocaine on VTA and NAc neurons. Chronic cocaine also produces characteristic changes in a number of phosphoproteins in the these two brain regions, prominent among which is tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine. The purpose of the proposed studies is to further characterize cocaine regulation of these intracellular messengers with respect to the time course, dose dependence, and pharmacological and anatomical specificity of cocaine action. These studies will provide information concerning the role played by adaptations of the intracellular messengers in cocaine action. Preliminary studies have also shown that some of the adaptations to chronic cocaine involve regulation of mRNA levels, consistent with the possibility that these changes occur, at least in part, at the level of gene expression. Indeed, we have found that chronic cocaine decreases the ability of an acute cocaine injection to induce the transcription factor Fos in the NAc. Proposed studies will further characterize cocaine regulation of this and other classes of transcription factors to learn more about the pathways through which cocaine regulates gene expression. The proposed investigations, aimed at characterizing cocaine-induced adaptations in intracellular messengers and gene expression in brain reward regions, will lead to a progressively more complete understanding, at the molecular level, of the mechanisms underlying cocaine abuse and addiction.
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