Our past studies have shown the NMDA receptor-dependent processes in the adolescent rat are far more sensitive to acute ethanol than the same processes in adults. However, since NMDA-mediated functions are critical for proper brain development, we were concerned that adolescent ethanol exposure, especially the repeated, intermittent use that characterizes the behavior of many adolescent drinkers, would produce effects that far outlasted the periods of acute intoxication and withdrawal. There is currently no information about the enduring neurobiological consequences of such ethanol exposure. We therefore conducted preliminary studies which examined adults rats that had been subjected to repeated intoxications and withdrawal (binge pattern intoxication) while they were adolescents, and, for comparison, we studied adults exposed as adults. As we report later in this proposal, the preliminary result showed that repeated exposure to a moderate ethanol dose during adolescence (but not during adulthood) caused impaired spatial memory and hippocampal long-term potentiation (LTP) that lasted into maturity. The following Specific Aims describe four sets of experiments that are designed to assess the neurobiological mechanisms by which intermittent ethanol exposure during adolescence disrupts normal function in adult rats. The first specific aim is designed to refine the model system and identify the optimum conditions for producing the learning deficits. It tests the hypothesis that intermittent ethanol exposure during adolescence causes learning problems later in life. The second specific aim examines the electrophysiological conditions of the hippocampus at several points during the exposure paradigm, and tests the hypothesis that repeated ethanol intoxication and withdrawal disrupts proper NMDA function by causing suppression and then rebound enhancement of NMDA receptor- mediated synaptic potentials with the repeated exposures. The third specific aims examines several types of neural plasticity in the hippocampus, and tests the hypothesis that the learning problems in maturity derive from abnormal manifestations of synaptic plasticity. If neuroplasticity is found to be abnormal, these experiments will point the way to further analytical experiments to explore the deficient mechanisms. The fourth specific aims examines the morphology of the hippocampus after intermittent ethanol exposure in adolescence and adulthood and tests the hypothesis that learning is disrupted by hippocampal neuronal death consequent to alterations in NMDA function.
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