Drugs of abuse, such as cocaine, can elicit compulsive drug seeking behaviors upon repeated exposure and widespread cocaine abuse creates one of the foremost public health problems in this country. Understanding the molecular mechanisms underlying the behavioral and the neuroplastic changes caused by cocaine is crucial for developing methods for the prevention and treatment of drug abuse. Enduring behavioral changes such as behavioral sensitization can be induced in rodents by repeated cocaine exposure. The neurobiological mechanisms underlying such behavioral changes are associated with the brain mesolimbic dopamine (DA) pathway. The longlasting behavioral effects of repeated cocaine exposure are highly likely to be associated with underlying changes in gene expression. However, the exact molecular changes that occur in response to long-term cocaine exposure remain unclear. Based on work from our own laboratory and from others, we hypothesize that changes in gene expression mediated through the DA D1 and D3 receptors play crucial roles in the behavioral changes induced by repeated cocaine administration. We propose to combine the use of unique animal models for cocaine actions, namely, D1 and D3 receptor mutant mice, with cDNA microarray technology to test the above hypothesis. Successful completion of this proposal will pave the way for testing the physiological significance of the molecular changes in cocaine-induced neuroplasticity in the future. The combined use of DA receptor mutant mice which exhibit altered behavioral responses to cocaine, with cDNA microarray technology, and proper physiological testing of the putative target genes has tremendous potential to provide novel insights into the molecular basis of compulsive drug seeking behaviors.
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