Long-term ethanol abuse and withdrawal in humans is associated with deleterious effects on neuronal function, including neurodegeneration that may be consequences of dysregulated Ca2+ homeostasis. This is reflected in elevated function of neuronal NMDA receptors and voltage-operated Ca2+ channels (VOCC). During ethanol withdrawal, increased function of these channels likely contribute to the accumulation of toxic levels of Ca2+ in neurons. The proposed studies are designed to elucidate mechanisms of ethanol-associated neuronal damage as they related to changes in neuronal Ca2+ buffeting. Radioligand binding and functional assays of radiolabeled Ca2+ entry into neurons will examine changes in neuronal density and function of NMDAr and VOCC in response to ethanol and correlated these changes with neuronal damage in cultured neurons of the rat hippocampus. Further, ethanol-induced reductions in glucose utilization, ATP content, and activity of neuronal Ca2+-ATPases will also be examined using autoradiography and functional assays, as these may represent effects of ethanol which reduce the efflux of Ca2+ following neuronal accumulation. Finally, recent evidence suggests that exposure to the nicotinic acetylcholine receptor agonist, (-)-nicotine, may be of benefit in reducing neuronal damage produced by ethanol abuse and/or withdrawal. It is hypothesized that this benefit is provided, in part, by preventing adaptive changes to ethanol which may increase intracellular accumulation of Ca2+ during periods of ethanol withdrawal. Indeed, this may be one reason underlying the close association between ethanol abuse and cigarette smoking. Thus, the ability of (-)-nicotine to prevent the effects of ethanol described above will be evaluated. It is intended that by conducting these studies, a better understanding of the mechanisms associated with ethanol abuse and withdrawal associated neurodegeneration will be provided and that the study of (-)-nicotine will aid in suggesting novel means of attenuating these effects. In particular, exposure to agents which interact with nicotinic receptors may be useful in this regard and, possibly, may be useful in reducing the incidence of cigarette smoking during chronic ethanol abuse.
