The goal of the proposed research is to gain understanding of the pathophysiological activities of ethanol in the brain, by studying the effects of ethanol on the NR2 subunits of the ionotropic glutamate N-methyl D-Aspartate (NMDA) receptor channel. The NMDA receptor is a heteromer comprised of the obligatory NR1 subunit and different combination of NR2 subunits (NR2A-D), with the major subunits in the brain being NR2A and NR2B. The cytoplasmic tails of NR2A and NR2B are phosphorylated by the tyrosine kinases Fyn or Src, and phosphorylation modulates the activity of the channel. The NMDA receptor is an important mediator of the activities of ethanol in the brain. Miyakawa and colleagues have reported that systemic administration of ethanol in mice results in tyrosine phosphorylation of hippocampal NR2B by Fyn kinase (Miyakawa et. al., 1997). Similarly, we have found that ethanol leads to phosphorylation of NR2B on tyrosine residues in isolated rat hippocampal slice preparations. We therefore hypothesize that induction of NR2B and possibly NR2A phosphorylation will play an important role in the pathophysiological effects of ethanol. In this study we propose to pursue four specific goals in an effort to better understand the biochemical, physiological and behavioral consequences of ethanol exposure mediated through the NMDA receptor system. First, we will study the spatial and temporal localization of ethanol induced NMDA receptor tyrosine phosphorylation in the brain. Second, we will examine the role of kinases and scaffolding proteins in ethanol induced NMDA receptor phosphorylation. Third, we will characterize the physiological consequences of ethanol induced NMDA receptor phosphorylation. Finally, we will test possible behavioral consequences of ethanol-induced NMDA receptor phosphorylation. Our long term goal is to understand the molecular mechanism of ethanol activities that contribute to the development of disease states associated with alcoholism, in order identify targets for the development of new medications to treat alcoholism.
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