project proposes to continue cellular studies of the role of neurotransmitters and their receptors in alcohol drinking and dependence, and is based on behavioral findings that the central amygdala nucleus (CeA) is a key brain area involved in stress reactions and alcohol dependence. These behaviors involve several transmitters, including GABA, glutamate, CRF, opioids, endocannabinoids (eCBs) and neuropeptide Y (NPY). With the rationale that the synapse is the most sensitive site of ethanol action, and particularly those synapses in CeA mediated or regulated by these transmitters, we hypothesize that these same neuropharmacological systems within the CeA are involved in excessive alcohol drinking and dependence. Therefore, we propose 3 Specific Aims to clarify the cellular underpinnings of these behaviors, using in vitro electrophysiological recording and in vivo microdialysis in CeA neurons of 2 TSRI-ARC rat models of selfadministered binge drinking and chronic ethanol-induced dependence (CEID), by studying: 1) the synaptic and cellular effects and interactions of opioids with CRF and acute and chronic ethanol exposure via these binge and dependence models. 2) the effects and interactions of cannabinoids and eCBs with CRF and acute and chronic ethanol exposure via these two models;and 3) the effects and interactions of NPY with CRF and acute ethanol in dependence, withdrawal and protracted abstinence. The electrophysiological studies will use CeA brain slices and involve standard intracellular and whole-cell clamp methods and a battery of measures to assess the pre- versus postsynaptic sites of action of ethanol and ligand effects. Microdialysis will be used to verify transmitter release. This project should provide important new information on the possible sequelae of ethanol binge drinking to dependence, at the cellular, synaptic and ion channel levels.
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