Although alcohol is the most widely used and abused drug in our society today, the mechanisms which underlie its central pharmacological (intoxication, anesthesia) and toxicological (brain damage, memory deficits) effects are largely unknown. An area of emerging importance in understanding the neurochemical mechanisms which mediate or are consequent to ethanol use and abuse is that of excitatory amino acid (EAA) function. In particular, a subtype of EAA receptor, the N-methyl-D-aspartate (NMDA) receptor, is implicated in learning, memory, and neurodegenerative processes. Our preliminary data suggest that ethanol, at concentrations which are consistent with its pharmacological range achieved in vivo (10-60 mM), inhibits NMDA receptor function. The major aim of this proposal is to define the site and mechanism of ethanol's inhibitory effect on NMDA receptor function at the molecular level. Functional assays (NMDA-stimulated neurotransmitter release and NMDA-induced inhibition of phosphoinositide hydrolysis in rat brain slices) in conjunction with radioligand binding techniques will establish whether ethanol is acting at one or more of the proposed sites which modulate NMDA receptor function (glycine, polyamine, zinc). Furthermore, studies are proposed to determine if acute or chronic ethanol administration in vivo alters NMDA receptor function. In addition to the in vitro studies, in vivo microdialysis measurements will be used to determine the effects of ethanol on NMDA mediated responses (changes in extracellular catecholamine levels) in freely moving animals. These microdialysis studies will thus provide a necessary link between the in vitro effects of ethanol and the effects of ethanol in vivo on NMDA mediated processes. The knowledge gained from these studies will contribute to our understanding of the molecular mechanisms of an important receptor system in the brain at a basic level. In addition, information will also be gained about the possible role of this system in ethanol-induced neuronal adaptation or damage and may lead to new therapeutic approaches for the treatment of alcohol related problems.
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