EXCEED THE SPACE PROVIDED. The molecular basis underlying the development of tolerance and physical-dependence to ethanol is yet to be defined. There is evidence for involvement of GABAA and NMDA receptors in the behavioral effects of ethanol, and in the development of tolerance and physical-dependence. Our studies are aimed at defining the potential molecular adaptive mechanisms by which chronic ethanol and chronic intermittent (CIE) ethanol treatments affect GABAA and NMDA receptor systems. Our main hypothesis is that chronic ethanol and CIE treatments produce differential alterations of the GABAA and NMDA receptor subunits, with increases in some, decreases in some and/or no changes in some of the subunits. This could result in altered receptor isoforms/ receptor assemblies, and/or affect the phosphorylation state of some of these subunits. We will utilize both in vitro and in vivo approaches. We will examine the effects of chronic and CIE treatments on subunit mRNA and polypeptide levels of GABAA and NMDA receptors, effects of chronic ethanol treatment on native GABAA and NMDA receptor assemblies, and determine if tyrosine-kinase mediatedphosphorylation of the GABAA and NMDA receptor subunits is affected by acute, chronic and/or CIE treatments. We will utilize cultured cortical neurons and whole animal studies. A major advantage of the cultured neurons is that they reflect the diversity of cell types of intact CNS, and provide an ideal in vitro model to study chronic drug effects. For native receptor assembly studies, we will utilize chronic ethanol treatment to rats and examine changes in discrete brain regions. This is necessitated by the fact that we will explore changes in adult native receptor assemblies, and examine effects in several regions of the brain that contain different receptor assemblies of GABAA and NMDA receptors. The following specific aims will be examined: 1) What are the consequences of CIE treatment on the GABAA and NMDA receptor subunit mRNA and polypeptide levels? 2) Which native GABAA and NMDA receptor assemblies are affected by chronic ethanol treatment? and 3) Do acute, chronic, and CIE treatments alter the Fyn-tyrosine kinase mediated phosphorylation of the NMDA and GABAA receptors? PERFORMANCE SITE ========================================Section End===========================================
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