The goal of this proposal is to investigate the inhibitory effects of ethanol on N-methyl-D-aspartate-evoked neuronal activity in vivo. This proposal pursues recent in vivo studies in our laboratory showing that ethanol, throughout a wide range of behaviorally relevant doses, inhibits the excitatory effects of N-methyl-D-aspartate (NMDA) in only a subset of neurons in the medial septum. This finding indicates that there exist both ethanol-sensitive and ethanol-insensitive NMDA-activated neurons in the medial septum. This proposal will test implications of the hypothesis that there exist both ethanol-sensitive and ethanol-insensitive NMDA activated neurons in brain by investigating 1) whether ethanol specifically inhibits medial septa] neuronal activity evoked by agonists of the NMDA receptor subtype of the glutamate receptor or, if not, whether differences in ethanol sensitivity occur in neurons activated by agonists of kainate and quisqualate glutamate receptor subtypes, 2) whether differences in ethanol sensitivity of NMDA-activated medial septa] neurons are due to local effects or effects of neural circuits, and 3) whether ethanol-sensitive and ethanol-insensitive NMDA-activated neurons exist at selected brain sites other than the medial septum and, if so, whether the proportion of neurons sensitive to ethanol varies systematically at these sites depending on NMDA receptor subpopulation distributions. This third approach permits testing of the hypothesis that the lack of inhibition by ethanol of responses to NMDA in some medial septal neurons is due to the presence of two types of NMDA receptors, one ethanol-sensitive, the other ethanol-insensitive.
