The goal of this proposal is to determine the effects of ethanol on different N-methyl-D-aspartate (NMDA) receptor subtypes. NMDA receptors are involved in a wide variety of normal and pathological processes in the CNS. Potent and selective inhibition of NMDA receptor activity may underlie many of the cellular and behavioral effects of ethanol. Regional specificity of ethanol on NMDA-mediated responses in the brain has been reported, suggesting that ethanol interacts with specific subpopulations or subtypes of NMDA receptor. Recently, multiple subtypes of NMDA receptors with distinct anatomical distributions and pharmacological properties have been identified. A clear understanding of the physiological effects of ethanol on the CNS requires identification of the NMDA receptor subtypes that are targets for ethanol action. the studies proposed here will determine, 1) the nature and specificity of ethanol's interaction with native NMDA receptor subtypes in rat brain, 2) the physiological effects of ethanol on distinct rat brain NMDA receptor subtypes expressed in Xenopus oocytes, and 3) the nature of the interaction of ethanol with the recently cloned NMDA receptor subtype, NMDAR1, using Xenopus oocyte and mammalian cell expression, and the relationship between NMDAR1 and pharmacologically- defined NMDA receptor subtypes. Additionally, these studies will identify the neuronal systems sensitive to ethanol and will lay the groundwork for future studies to examine the regulation of NMDA receptor subtypes by chronic ethanol exposure and the structural determinants of ethanol interactions with the NMDA receptor. It is my objective to develop expertise in the molecular mechanism of action of ethanol on ligand-gated ion channels. Ligand-gated ion channels are important sites of action for ethanol. However, identifying the molecular targets for ethanol is complicated by the complexity of ligand-gated ion channels. Many of these ion channels are oligomeric complexes with significant subunit heterogeneity. Recent evidence suggests that subunit composition may confer specific pharmacological, physiological, anatomical and regulatory properties on a given receptor. Thus, thorough investigation of ethanol interactions with ligand-gated ion channels requires a multidisciplinary approach.
