Alcohol is the most prevalent, and in some ways, the least well understood of the drugs of abuse. Chronic exposure to ethanol has been sown to upregulate certain neurotransmitter receptors, including the glutamatergic N-methyl-D-aspartate (NMDA) receptor and certain of its subunits. It is not known whether this change has anatomic specificity, or what effects these changes have on the expression of NMDA-dependent long-term potentiation (LTP), a proposed cellular correlate of learning. It is also unknown whether these changes might persist beyond the period of exposure, and thereby contribute to later effects of ethanol, such as craving and relapse. The studies proposed here use a combined electrophysiological and anatomic approach to study the effects of chronic ethanol exposure and withdrawal on the N-methyl-D-aspartate receptor in single neurons in a hippocampal slice preparation in the mouse. The studies aim first to describe in detail the subcellular distribution of NMDA receptor subunits in mouse hippocampal area CA3 using immunocytochemical methods in intracellularly labeled neurons, and to investigate whether this distribution changes with the induction of LTP. Then, hippocampal slices from mice that have been chronically exposed to ethanol will be analyzed for differences in this anatomic distribution, and for effects of this treatment on LTP. Finally, slices from mice that have been subjected to chronic ethanol treatment and withdrawn for several weeks will be similarly analyzed, as a model of relapse. It is hoped that these studies will provide crucial insight into the subcellular distribution and function of the NMDA receptor and its subunits, and help define their role in chronic alcoholism and relapse.
