The overall objective of this application is to determine the role specific subcortical inputs to the hippocampus may have in mediating the acute intoxicating actions of ethanol on this structure, a brain region known to be highly sensitive to the neuropharmacology of ethanol. These in vivo studies will complement the more prevalent in vitro electrophysiological investigations of ethanol actions on the hippocampus. Moreover, these investigation will provide new information regarding ethanol actions on extrinsic modulatory inputs to the hippocampus, only observable in the intact preparation. Our proposed studies are designed to test three major hypotheses: 1) That the hippocampus exhibits regional and cell specific sensitivity to acute intoxicating levels of ethanol; 2) The subcortical inputs to the hippocampus selectively influence the actions of ethanol on recurrent inhibition and plasticity in the dentate gyrus; and 3) That dopamine, originating from ventral tegmental neuronal projection sites, functions as a critical neurotransmitter in the neuropharmacological actions of ethanol on the hippocampus. We will employ electrophysiological analysis of the effects of acute local and systemic ethanol on hippocampal single- unit activity and synaptically-evoked events in the in vivo anesthetized rat. We will investigate the effects of in situ microelectrophoretic ethanol in the medial septum and ventral tegmental area, subcortical structures with relevant input to the hippocampus, on recurrent inhibition and ethanol on medial septum and ventral tegmental area conditioning of afferent-evoked responses in the three sub-regions of the hippocampus and will determine the interaction of ethanol with the major neurotransmitter of these pathways: acetylcholine, GABA and dopamine. We hypothesize that this in vivo hippocampal model provides a unique opportunity to analyze the actions of ethanol on regional and local circuitry and their neurochemical substrates implicated in the cognitive and reinforcing properties of ethanol.
