This proposal seeks to study the neurobiological basis of alcoholism by investigating changes in gene expression in conjunction with acute and chronic ethanol exposure, acute and protracted ethanol withdrawal, ethanol reinforcement in rats operantly self-administrating ethanol, and the reinstatement of ethanol-seeking behavior by alcohol-related environmental stimuli. Gene expression will be investigated in brain regions relevant to alcohol's reinforcing and addictive actions. Such regions will be collected by laser capture microdissection and will include the shell of the nucleus accumbens, the central and basolateral nuclei of the amygdala, the medial prefrontal cortex, the ventral tegmental area and the bed nucleus of the stria terminalis. The microarray technology selected (Affymetrix) will permit a systematic quantitative screening of gene expression, allowing for the cross-comparison of gene expression levels among the different experimental conditions and brain regions. A comprehensive database accessible to other investigators will be constructed with the results obtained. The profiling of gene expression patterns associated with the different stages of the proposed animal models will provide insight into the functional regulation of the cellular systems involved, and will have direct implications for the development of pharmacotherapeutic treatment strategies in the prevention of compulsive ethanol-seeking behavior and relapse.
