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 (EtOH) which contribute to acute intoxication. Ethanol inhibits the function of N-methyl-D-aspartate (NMDA) type glutamate receptors. In most neuronal preparations examined to date, this inhibition is selective with respect to other glutamate receptors. However, inhibition of the function of non-NMDA, AMPA/kainate type glutamate receptors by intoxicating concentrations of EtOH has been observed in some cases. Glutamate is the major excitatory neurotransmitter in the mammalian CNS, and has been implicated in a number of CNS functions including motor control, information storage, processing sensory information and respiratory control. Ethanol inhibition of responses mediated by NMDA receptors probably contributes to its cognitive impairing and sedative effects, while inhibition of other glutamate receptors could contribute to EtOH-induced anesthesia and respiratory depression. The mechanisms of EtOH action on glutamate receptors are not well understood. In addition, we known little about the molecular properties of glutamate receptors which contribute to EtOH sensitivity. The relationship between the behavioral effects of EtOH and EtOH actions on glutamate receptors in different CNS regions also requires further investigation. Thus the hypotheses to be tested are: 1) That different subtypes of NMDA and AMPA/kainate glutamate receptors are differentially sensitive to EtOH, and that neurons containing these different receptor subtypes will show differential EtOH sensitivity; 2) That EtOH affects specific kinetic aspects of glutamate receptor/channel function and will inhibit the function of single NMDA receptor/channels.; 3) That the potency and selectivity of EtOH inhibition of glutamate receptor-mediated responses differs in neurons from different areas of CNS; Experiments to test the first two hypotheses will be carried out using whole-cell and single channel patch clamp recording techniques in neurons from mammalian CNS as well as human embryonic kidney (HEK 293) cells expressing specific recombinant glutamate receptors. Regional variability n the potency and selectivity of EtOH actions will be performed using whole-cell patch-clamp recording from acutely isolated rat brain neurons as well as from extracellular and whole-cell recording from rat brain slices. There is ample evidence that glutamate receptor inhibition plays an important role in acute intoxication. The proposed experiments will contribute to our knowledge of the molecular basis of EtOH effects on these receptors. These experiments will also reveal which regions of the brain and which glutamate receptor subtypes are most affected by this inhibitory action of EtOH. 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 EtOH.