Project Summary Alcohol misuse levies a major impact on public health, yet the brain mechanisms underlying how this substance drives its misuse are poorly understood. This proposal seeks to discover a novel mechanism underlying the rewarding properties of alcohol. Data derived from this study stand to provide novel treatment strategies aimed at blunting the rewarding effects of alcohol in those suffering from alcohol use disorders. The motivation to seek and acquire rewards is encoded by the output of a key reward integration center in the brain, the nucleus accumbens. Inhibitory synapses in this structure powerfully gate its output. Our preliminary experimentation indicates that alcohol pathologically disinhibits the nucleus accumbens by hijacking a form of synaptic plasticity at inhibitory synapses. This novel mechanism positions alcohol as a pathological enhancer of nucleus accumbens output and reward encoding. To elucidate this further, we propose three aims of investigation using cutting-edge approaches: 1) to determine the neural circuit components necessary for driving ethanol enhancement of this synaptic plasticity; 2) to determine the molecular mechanism mediating ethanol enhancement of this form of plasticity and; 3) to causally determine how ethanol enhances NAc-iLTD reward encoding in vivo. The results of this study stand to significantly advance our understanding of alcohol action in the brain and provide important insight to myriad neuropsychiatric disorders involving nucleus accumbens synaptic dysplasticity.