The primary objective of this project is to understand the neuronal, cellular and synaptic mechanisms underlying alcohol intoxication and dependence, using intracellular and patch-clamp recording in brain slices and in vivo microdialysis. A central hypothesis is that adaptive changes in synapses cause alcohol dependence. We also hypothesize that neuroadaptations in the GABAergic system play a major role in alcohol reinforcing actions. Our past research has centered on neurons of the central nucleus of the amygdala (CeA), because behavioral studies suggest that the amygdala, and its connections to the NAcc and bed nucleus of the stria terminalis, termed the 'extended amygdala,' play a major role in the acute reinforcing effects of ethanol and in the anxiogenic response to ethanol withdrawal. Our planned studies are based on the following rationale: 1) Acute ethanol markedly enhances GABAergic neurotransmission in CeA through the activation of CRF1 receptors. We present the first direct evidence that this ethanol-induced increase in GABAergic response is in part due to increased GABA release. 2) Our preliminary data also indicate that chronic ethanol treatment (GET) greatly enhances baseline GABAergic tone in the CeA. 3) Despite this large increase in basal GABA release, there is a lack of tolerance to acute ethanol-induced GABA release in CeA of GET rats. 4) Our preliminary evidence of neuroadaptive changes in the CRF system and in GABAB receptors in modulating synaptic efficacy following GET. Therefore in this application we propose to study the cellular and molecular basis of ethanol interactions with GABAergic transmission using a multidisciplinary approach.
Specific Aims 1 and 2 will test, in vitro and in vivo, the possible involvement of presynaptic CRF receptors, membrane Ca++ channel and their transduction mechanisms coupled to the regulation of GABA release machinery in the effect of acute (Aim 1) and chronic (Aim 2) ethanol in CeA neurons. Understanding the specific presynaptic mechanisms underlying ethanol enhancement of GABA IPSPs induced by both acute and chronic ethanol represents a new challenge for alcohol research and a possible target for the development of therapeutic compounds for the treatment of alcoholism. ? ?
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