The goal of the present component is to address the molecular mechanisms underlying alcohol-induced neuroadaptive changes. Current knowledge of the molecular basis of alcohol action on the central nervous system suggests that phenotypic changes brought by the altered expression of specific genes are central to alcohol neuroadaptation. The ability of alcohol to directly and/or indirectly affect specific signal transduction pathways and transcriptional regulators in selected neuronal systems is believed to be key to the process. The MAPK/ERK signal transduction pathway has been shown to be involved in biological responses of diverse stimuli such as hormones, neurotransmitters and membrane depolarization. This pathway is believed to be a major link between events at the level of the plasma membrane and long-term phenotypic changes induced by extracellular signals. We have observed that at concentrations meaningful to human consumption, alcohol is capable of potentiating MAPK/ERK activation in vitro in the affected in selected brain regions during specific stages of chronic and acute alcohol exposure models. We now propose the following: to investigate the molecular basis for alcohol interaction with the MAPK/ERK signal transduction pathway in vitro, by biochemical and pharmacological techniques; and to extend our study of the regulation of this pathway in vivo models of acute and chronic alcohol exposure as well as in withdrawal and relapse paradigms with special reference to the brain reward system. These two complementary approaches (in vitro/in vivo) will form the foundations for the investigation of the functional role played by this pathway in long-term changes associated with alcohol use. These studies will improve our understanding of the molecular mechanisms by which alcohol affects brain function and, in turn, may lead to the development of novel and more effective therapeutic interventions.