ETHANOL INHIBITION OF NMDA RECEPTOR-MEDIATED RESPONSES

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The aim of the research project is to further our understanding of the neuronal effects of ethanol which contribute to acute intoxication. Recent studies have shown that ethanol selectively inhibits responses mediated by the N-methyl-D-aspartate (NMDA) class of receptor for the neurotransmitter glutamate. Ethanol appears to have little effect on responses mediated by the kainate- and quisqualate-type glutamate receptors. Glutamate is the major excitatory neurotransmitter in the mammalian CNS, and the NMDA storage. Ethanol inhibition of responses mediated by this receptor probably contributes to its cognitive impairing and sedative effects. The mechanism of ethanol's action on the NMDA receptor is not well understood, although it has been proposed that ethanol interacts with the glycine modulatory site on the NMDA receptor/channel complex. In addition, the relationship of the behavioral effects of different sedative/hypnotic agents to their actions on glutamate receptors is not well understood. Finally, the relative potency of ethanol's action on glutamate receptors in different CNS regions has not been adequately described. Thus the hypotheses to be tested are: 1) that ethanol inhibits NMDA receptor- mediated responses via an interaction with the glycine modulatory site or other sites important for the function of the NMDA receptor; 2) that other sedative/hypnotic agents and ethanol-like compounds differ from ethanol in the potency and selectivity of their actions on glutamate receptor-mediated responses; 3) that ethanol alters the function on single NMDA-activated ion channels; and 4) that ethanol has a different potency and selectivity for inhibiting NMDA receptor-mediated responses in neurons from different CNS regions. Experiments to test these hypotheses will be carried out using whole-cell and single-channel patch-clamp recording techniques in neurons from mammalian CNS. Experiments examining ethanol interactions with modulatory sites on the NMDA receptor, the effects of sedative/hypnotic and ethanol-like compounds and ethanol's actions on single NMDA receptor-gated ion channels will be performed in neurons from fetal mouse hippocampus grown in cell culture. Experiments examining regional variation in the potency and selectivity of ethanol's actions will be performed in brain slices from rat. There is mounting evidence that ethanol inhibition of NMDA receptor- mediated responses contributes to acute intoxication. The proposed experiments will contribute to our knowledge of the molecular mechanism(s) of ethanol's effect on NMDA receptor function. In addition, these experiments will reveal which regions of the CNS are most affected by this inhibitory action of ethanol. It is hoped that the outcome of these experiments will provide a basis for the development of treatments which can counteract some of the intoxicating effects of ethanol.