ETHANOL EFFECTS ON GLYCINE RECEPTOR/CHANNEL FUNCTION

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Ethanol (EtOH) is an effective brain depressant and an additive drug. Emerging evidence suggests that glycine receptor/channels (GlyRs) are sensitive to pharmacologically relevant concentrations of EtOH. Since glycine inhibits neuronal activity, potentiation of GlyR function would be expected to enhance neuronal inhibition and perhaps contribute to the neuronal depressant effects of EtOH. Therefore, we propose to examine the effects of EtOH on glycine-induced responses of dopaminergic neurons from the ventral tegmental area (VTA) of the brain, the reward center for drug abuse. The overall objective of this study is to investigate the mechanisms by which EtOH alteration of GlyR function contributes to the central nervous system (CNS) consequences of alcohol in vivo. To achieve this objective the following three hypotheses will be tested. HYPOTHESIS I is that EtOH interacts with the GlyR. EtOH regulates the excitability of dopaminergic neurons by altering functions of GlyRs. HYPOTHESIS II is that EtOH interactions with the GlyR are modulated by the protein phosphorylation status of the GlyR, the intracellular activity of PKA, PKC and G-proteins. HYPOTHESIS III is that GlyR structure, intracellular C1-concentration of dopaminergic neurons and, consequently, glycine-induced responses and their response to EtOH change with development. These hypotheses will be tested on VTA neurons freshly isolated from both neonatal and mature rats. Whole-cell patch- clamp technique (especially gramicidin perforated patch technique) will be used to record glycine-induced responses, including membrane current, potential and the alteration of spontaneous firing in the absence and presence of EtOH. Specific activators and inhibitors of protein kinases A and C and of G-proteins will be used to identify the enzyme pathways involved in any effects, of EtOH on GlyRs. These studies will significantly advance our understanding of the effects of EtOH on CNS GlyRs at the molecular and cellular levels. A better knowledge of the actions of EtOH in the brain will improve our understanding of related reinforcement mechanisms, which will, in turn, facilitate the identification of strategies which might be of value in the treatment of alcohol abuse and fetal alcohol syndrome.