This project will continue cellular studies of the role of synaptic transmitters in the intoxicating effects of ethanol, and initiate investigations on the cellular substrate of alcohol addiction. The rationale behind the first approach is the considerable literature showing the synapse to be the most sensitive site of ethanol action, and evidence for pronounced effects of intoxicating doses of ethanol on the functions of several transmitters. For example, our studies have revealed ethanol effects on cholinergic and somatostatinergic function, but not on GABAergic transmission. The second approach is based on behavioral findings with heroine, cocaine and alcohol, suggesting that the nucleus accumbens (NAcc) is a key area in the reinforcing properties of these drugs, and that these properties also may involve several transmitter candidates. We propose the following five sets of experiments: 1) continue and complete tests of ethanol effects on cholinergic and somatostatinergic function; 2) seek interactions between ethanol and several transmitter candidates in the NAcc, using new recording and cell identification methods to compare ethanol effects in different neuronal cell types; 3) test effects of the 'anti-alcoholism' drug Ca-AOTA (calcium-acetylhomotaurinate; AOTAL; acamprosate) on membrane properties and neurotransmission in hippocampal and NAcc neurons of naive and ethanol-withdrawn animals; 4) compare ethanol effects on NAcc neurons from the ethanol-preferring (P) and non-preferring (NP) rat strains developed by the Li-Lumeng group. These studies will use hippocampal and NAcc brain slices and involve standard intracellular (current- and voltage-clamp) and new """"""""patchslice"""""""" whole-cell clamp methods. The powerful new infrared DIC-videomicroscopic method will be used to clearly distinguish morphologically different cells types for comparison of electrophysiological and pharmacological properties and to determine if the frequent negative electrophysiological findings of ethanol-transmitter interactions (e.g., ethanol-GABA) arise from cell sampling problems. Other transmitter candidates to be examined for ethanol interactions or mimicry include primarily glutamate, dopamine, and serotonin (5-HT), transmitters under study by other ARC units, although acetylcholine and somatostatin may be tested later. We believe these studies will not only provide important new information on possible sequelae of ethanol intoxication at the cellular level, but, by virtue of comparisons of ethanol and Ca-AOTA actions in normal, P and NP rats, may also provide clues as to the cellular and ion channel correlates of ethanol dependence.
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