We have pursued electrophysiological studies of the role of synaptic transmitters, neuropeptides and their receptors in alcohol effects, with the rationale that these elements are the most sensitive sites of ethanol action. This project is based on behavioral findings that the nucleus accumbens (Nace) and extended amygdala are key areas in the reinforcing properties of abused drugs, and that these properties also may involve several transmitters (e.g., GABA, glutamate) and neuropeptides (e.g., CRF and opioids). The amygdala has been implicated in motivated behaviors and anxiety states, and it is hypothesized that these same neuropharmacological systems within the extended amygdala mediate the increases in ethanol self-administration that occur during withdrawal from chronic ethanol. Therefore, we propose several sets of experiments: 1) To begin in vitro brain slice studies of acute and chronic ethanol effects on membrane and synaptic properties of central amygdala (CeA) neurons and NAcc neurons in the mouse for comparison to our rat data, and to prepare for studies of murine genetic models. 2) To determine the role of CRF receptors, whose expression may be responsible for excessive alcohol consumption, by examining extended amygdala network and cellular functioning in brain slices taken from mice with knockouts for brain CRF-I receptors. 3) To determine the role of opiate receptors that could be responsible for excessive alcohol consumption, by examining extended amygdala network and cellular functioning in brain slices taken from rnice with knockouts for brain mu opiate and, later, delta opiate receptors. These studies will use amygdala and NAce brain slices and involve standard intracellular (current- and voltage-clamp) and """"""""patch-slice"""""""" whole-cell clamp methods. The infrared DIC-videoniieroseopic method will be used to identify morphologically different cells types for comparison to electrophysiological and pharmacological properties. We will record evoked, pharmacologically-isolated monosynaptic currents or potentials, and spontaneous and miniature synaptic events, to test the specificity and site of action of ethanol effects. These studies should provide important new information on possible sequelac of ethanol intoxication at the cellular level, and, by comparisons of ethanol and peptide actions in control, ethanol-withdrawn, protracted abstinence, and knockout models, will also provide clues as to the cellular and ion channel correlates of ethanol dependence.
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