Drug addiction is a chronic relapsing disease that is characterized by the compulsive seeking and taking of a drug despite known adverse consequences. A prominent feature of drug addiction is that it is a long- lasting condition. Effective treatment strategies of this disease depend on a thorough understanding of the molecular mechanisms underlying the persistent nature of drug-induced behaviors. Changes in gene expression through specific dopamine (DA) receptor subtypes have been thought to play a key part in mediating enduring neuroadaptations to repeated drug exposure. The immediate early gene product c-Fos is an ideal candidate to couple repeated cocaine stimuli to persistent neuroadaptation in the brain DA system by regulating gene expression. We have investigated these assumptions using novel genetically engineered mouse models and found that the DA D1 receptor mediates both the locomotor sensitization and the reinforcing effects of cocaine. The D1 receptor also mediates cocaine-induced neurophysiological responses, dendritic remodeling and gene expression changes in the brain, including c-fos and genes containing AP-1 binding sites in their promoter regions. Furthermore, proper c-Fos expression in D1 receptor-producing neurons contributes to cocaine-induced behavioral sensitization, dendritic remodeling and gene expression changes. Noticeably, mutations of the D1 receptor gene and c-fos share several common consequences following repeated cocaine injections. These findings led us to hypothesize that c- Fos is a significant intracellular signal transducer downstream of the D1 receptor that contributes to the behavioral effects of cocaine, and that c-Fos-regulated gene expression changes participate in persistent neuroadaptation to repeated exposure to cocaine. The overall goal of this proposal is to test the above hypothesis. We propose to determine the role of c-Fos in the behavioral effects of cocaine by combining the use of behavioral sensitization and self-administration paradigms with novel DA D1 receptor neuron- specific c-fos mutant and inducible c-fos mouse models. We also propose to identify D1 receptor-mediated and c-Fos-regulated gene expression changes that persist long after cocaine withdrawal. Successful completion of the proposed work will establish a molecular framework on how c-Fos couples repeated cocaine exposure to persistent behavioral changes and neuroadaptation by regulating specific gene expression in DA D1 receptor-expressing neurons in the brain. These experiments may provide novel insights into mechanisms underlying drug addiction and new strategies for the treatment of drug abuse.
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