The aim of the research project is to assess the contribution of specific ligand-gated ion channels in mediating the perceptible effects of ethanol in the CNS. Three of these receptor/channel complexes that are particularly sensitive to the effects of ethanol in in vitro assays are the GABAA receptor complex, the NMDA subtype of glutamate receptor complex, and the 5-HT3 subtype of serotonin receptor. These receptor systems encompass components of the major inhibitory and excitatory neurotransmitter systems, and a component of the serotonin system, implicated in many behavioral effects of ethanol. The interaction of ethanol with these receptor systems in electrophysiological and biochemical assays occurs at concentrations of 5-50 mM, corresponding to a range of blood ethanol concentrations associated with mild intoxication to loss of righting reflex. The sensitivity of these receptor-linked ion channels to ethanol indicates a specificity to the pharmacological actions of ethanol. The interaction of ethanol at several different receptor systems can be expected to give rise to a mixture of internal stimulus effects, composed of distinguishable component parts. Understanding how ethanol acts at each component receptor system to produce its discriminable effects will advance our understanding of ethanol's pharmacological actions and may be helpful in the design of potential pharmacotherapies to alter and possibly limit excessive ethanol intake. The proposed studies utilize the drug discrimination procedure to 1) determine the modulatory sites on the GABAA receptor complex that are sufficient to produce ethanol-like discriminative effects 2) determine if antagonism of NMDA transmission by compounds acting at the NMDA, channel, glycine or polyamine modulatory sites on the NMDA receptor complex results in similar discriminative stimulus effects as ethanol. 3) Determine the structural requirements of the 5-HT3 antagonists to block the discriminative effects of ethanol, and if this blockade can be due to action of the 5-HT3 antagonists at the nicotinic cholinergic or GABAA channels. 4) Determine if the dose of ethanol used in training the discrimination determines the relative contribution of each receptor system in mediating the discriminative effects of ethanol. 5) Whether a component of the compound discriminative stimulus effects of ethanol can be isolated from the action of ethanol at other receptor systems.
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