The Alcohol Center for Translational Genetics (ACTG) will identify novel proteins as targets for therapeutics for alcohol use disorders and will determine mechanisms by which they act to regulate excessive ethanol intake. Candidate proteins will be evaluated in ethanol self-administration procedures that model excessive binge drinking in humans, motivation to drink ethanol, and relapse. The anatomical focus will be on 3 brain regions, the nucleus accumbens, the amygdala, and the ventral tegmental area, which all play important roles in ethanol consumption and relapse. Based on findings during the current funding cycle that identified H-Ras/PI3 kinaseAKT/mTORC1 signaling as a key regulator of ethanol consumption, all Research Components will include experiments that test the relationship of the novel proteins with this pathway. Three research projects will focus on proteins new to alcohol research: SGK1, GSK-3 and others whose translation is regulated by mTORC1 (Component 4); PKM? and its direct substrates (Component 5); and orexin/hypocretin receptors (Component 6). An Administrative Core (Component 1) will manage ACTG functions. An Animal Behavior Core (Component 2) will perform studies of intermittent ethanol access in rats and mice and will provide assistance in rat operant self-administration procedures. A Vector and Imaging Core (Component 3) will provide state-of-the art services to generate viral vectors for transgenic expression or gene silencing, and to analyze transcript and protein abundance by laser capture microdissection, high resolution immunofluorescence, and quantitative fluorescent in situ hybridization for detecting mRNAs in dendrites. Two Pilot projects are planned. The first will test the hypothesis that delta opioid receptor mediated inhibition of GABA release decreases alcohol consumption in anxious alcoholics. The second will determine whether up-regulation of NMDA receptor activity, induced by excessive ethanol consumption, facilitates long-term potentiation in the dorsomedial striatum, and thereby enhances ethanol drinking and seeking. Collectively, the ACTG provides a unique opportunity for integrated study of novel proteins that may lead to the development of new treatments for alcohol use disorders in humans.