Ethanol produces internal stimulus effects that are reinforcing and that maintain either social or pathological drinking in a large number of individuals. The drug discrimination procedure is a particularly useful technique to characterize the receptor mechanisms that mediate the internal stimulus effects of drugs. The overall goal of the proposed research is to assess the contribution of specific ligand-gated ion channels (GABAA and NMDA) in mediating the mixed discriminative stimulus effects of ethanol. Thus, the aims of the present proposal are to continue the development of a model to characterize ethanol's direct and concurrent activity at a number of receptor systems and explore behavioral correlates of some newly identified cellular mechanisms of ethanol's activity. These five new Specific Aims are: l. To investigate the discriminative stimulus effects of ethanol mediated by NMDA and GABAA receptor systems as a function of ethanol training dose. 2. To investigate the optimal ligand to represent the modulatory effects of ethanol at the GABAA (or NMDA) receptor in characterizing receptor interactions. 3. To determine if discriminative stimulus effects that are unique to ethanol are due, in part, to an interaction between ethanol-sensitive GABAA and NMDA receptor systems. 4. To determine whether the ethanol-like effects of the 5-HTIB agonists are secondary to ethanol's effects of GABAA receptors. 5. To assess the potentiation of ethanol's activity at a ligand-gated ion channel by activating metabotropic receptors with drug discrimination. The immediate significance of the proposed studies will be to extend information on ethanol as a mixed stimulus in the CNS, composed of, but not limited to, actions at specific sites on ligand-gated ion channels. These findings will suggest variables that determine the effectiveness of pharmacological agents to block ethanol's stimulus effects, and may suggest the appropriate receptor system(s) to target.
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