Certain biological factors may increase risk individual for developing pathological alcohol consumption leading to alcohol abuse or alcoholism. Characterization of """"""""risk factors"""""""" is considered an important step in designing effective measures to identify susceptible individuals and prevent potential alcohol pathology. In this regard, acute tolerance to ethanol may play an important role in the genesis of psychological dependence. It has been proposed that acute tolerance to dysphoric CNS impairing actions of ethanol indirectly strengthens the reinforcing effects of the drug. At present, very little is known about the cellular mechanisms underlying acute tolerance to ethanol. Recently, we have identified a potential synaptic model of """"""""acute tolerance to ethanol"""""""" where the inhibitory action of the drug on NMDA-mediated dendritic EPSPs in the CA1 region of rat hippocampal slices is swiftly lost over as little as 15 min of continuing ethanol exposure. This project is an effort utilizing in vitro electrophysiological methods (extra- and intracellular or patch clamp recordings) to characterize and identify cellular mechanisms of this swift loss of ethanol inhibition. The time course of acute tolerance development and loss as well as its dependence on synaptic activation and pre- or postsynaptic plasticity involving neuromodulators will be determined. The likelihood that acute tolerance occurs to inhibitory effects of more potent alcohols (ie., 1-butanol and isopentanol) or can be induced in other brain regions (ie., dentate gyms, neocortex, nucleus accumbens and amygdala) will be examined. Finally, the impact of in vivo ethanol treatment leading to both acute intoxication and chronic functional tolerance and physical dependence on in vitro acute tolerance to ethanol will be evaluated. Together, these studies should help determine whether loss of ethanol inhibition of NMDA-mediated EPSPs is a useful in vitro model of acute tolerance and should test the hypothesis that """"""""acute tolerance in the slice develops due to postsynaptic mechanisms that block the inhibitory effects of ethanol on the NMDA receptor.""""""""
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