Both acute and chronic ingestion of ethanol result in multiple effects in the central nervous system (CNS) as well as in a variety of other organs such as liver and heart. In the CNS, there are both short and long term effects of chronic alcohol consumption such as intoxication, memory loss, tolerance to the acute intoxicating effects of ethanol, addiction, and dependence. The pleiotropic effects of ethanol exposure can be also observed at a molecular level; amounts and activities of components of several signal transduction systems are altered as a result of exposure to ethanol in a time- and dose-dependent manner. The molecular targets for ethanol and the mechanism by which ethanol-induced effects occur are largely unknown. However, studies from several laboratories indicate that the effects of ethanol are specific. This proposal is focused on protein kinase C (PKC) signaling pathway, a key pathway in the CNS. Short- and long-term exposures to ethanol specifically alter the level and activity of components of this key signal transduction system. There are multiple PKC isozymes that regulate important cellular functions and preliminary studies using a model of neuronal cells in culture suggest that ethanol exposure also results in changes in the subcellular localization of a specific PKC isozyme and its anchoring protein, RACK. The study of ethanol-induced changes in the CNS and their functional consequences is a particular challenge because individual brain regions and various cell types in each region express different PKC isozymes and have different sensitivities to ethanol. Here the investigator describes her plan to devise tools to identify the effects of ethanol in individual cells in situ. They will raise novel monoclonal antibodies (mcAbs) that will distinguish between states of activity of individual PKC isozymes as well as mcAbs to RACK. These mcAbs will be used in immunocytochemical studies of model neuronal cell culture systems as well as in brain of control and ethanol-treated mice. Such mcAbs will allow, for the first time, the determination of how ethanol affects the localization and activity of the components of this key signal transduction system in specific regions and cells in the brain. These studies will help elucidate the molecular basis of ethanol effects and alcoholism in man.
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