ETHANOL EFFECTS ON CALCIUM CHANNELS AND NMDA RECEPTORS

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This competing continuation project will continue to examine the effects of acute and chronic ethanol administration on calcium entry into neuronal preparations. The focus of the experiments will be to study the effects of ethanol on NMDA-stimulated calcium entry into dissociated brain cells. Studies will also be conducted on dihydropyridine-(L-type) and w-conotoxin- sensitive (N and L type) calcium channels and their interactions with NMDA receptors. NMDA-stimulated glutamate receptors in the brain appear to be involved in many important processes such as neuronal development, neuronal toxicity and learning and memory. Recent studies in our and other laboratories have shown that NMDA receptor-mediated processes in the brain are highly sensitive to inhibition by ethanol. The studies described in this application will characterize the sensitivity of NMDA-stimulated calcium entry into dissociated brain cells from brain regions known to have high, intermediate and low densities of NMDA receptors. Furthermore, mechanisms of ethanol's inhibitory effects on the NMDA receptor will be determined by studying the role of key modulatory sites (glycine co-agonist site, PCP-inhibitory site, Mg++ inhibitory site and the competitive receptor site) in activating NMDA function (by studying calcium entry) and receptor binding in the presence and absence of ethanol. Recent evidence suggests that there may be links between neuronal abnormalities associated with fetal alcohol exposure and alterations in number or function of NMDA receptors; thus, studies will be conducted to examine the effects of fetal alcohol exposure on NMDA-stimulated calcium entry into isolated dissociated neurons. Receptor binding studies will also be conducted on brain membranes isolated from fetal alcohol exposed rat pups to study its influence on NMDA-receptor modulation. Finally, studies will be conducted to examine the effects of chronic ethanol exposure in adult rats on NMDA- receptor modulation.