Ethanol is thought to act, in part, by enhancing GABAergic inhibitory neurotransmission and by decreasing glutamatergic synaptic excitation in the mammalian CNS. Much evidence also suggests that compensatory changes in these neurotransmitter systems develop in response to repeated ethanol exposure and that this synaptic adaptation contributes to some of the behavioral and cognitive changes associated with alcohol addiction. In this project, we will use in vitro patch clamp electrophysiology methods to study acute and longterm effects of ethanol on GABAergic and glutamatergic synaptic transmission in several brain regions within the meso-cortico-limbic circuitry that is thought to mediate ethanol's reinforcing effects. Aim 1 will test the hypothesis that a novel interaction between ethanol and presynaptic GABAB receptor function, first described in the rat hippocampus, also regulates the ethanol sensitivity of GABAergic synapses in the monkey hippocampus and the rat basolateral nucleus of the amygdala (BLA) and ventral tegmental area (VTA). Aim 2 will examine hippocampal synaptic neuroadaptation in a monkey model of excessive ethanol drinking. We expect that excessive ethanol exposure and withdrawal will result in a downregulation in GABAergic neurotransmission, an upregulation of NMDA-receptor-mediated synaptic excitation, and tolerance to the acute modulatory effects of ethanol on NMDA-, but not GABAA receptor-mediated synaptic responses. Aim 3 will employ a rodent model of excessive ethanol drinking to characterize synaptic adaptation in the hippocampus, BLA, and VTA following long-term ethanol exposure and withdrawal. Results of Aim 3 will permit a systematic comparison of ethanol-induced synaptic adaptation in the rat and monkey hippocampus. This aim will also test the hypothesis that there may be significant brain region differences in synaptic adaptation following ethanol exposure and withdrawal. Integration of the results of these studies with those of other projects within the Center may provide new insight into how synaptic communication in brain regions associated with ethanol self-administration is altered following excessive ethanol drinking. These studies may also identify specific characteristics of brain regions that are most vulnerable to ethanol-induced synaptic adaptation. Such findings may help clarify the neurophysiological mechanisms that contribute to abusive drinking behavior and possibly identify novel targets for the development of pharmacotherapies in the treatment of alcohol addiction.