ETHANOL INHIBITION OF NMDA RECEPTOR-MEDIATED RESPONSES

这项研究项目的目的是加深我们对 导致急性中毒的乙醇的神经元效应。近期 研究表明，乙醇选择性地抑制由 N-甲基-D-天冬氨酸(NMDA)类神经递质受体 谷氨酸。乙醇似乎对介导的反应几乎没有影响。 海人酸型和准品质酸型谷氨酸受体。谷氨酸是 哺乳动物中枢神经系统的主要兴奋性神经递质和NMDA 储藏室。乙醇对该受体介导的反应的抑制 可能与其认知受损和镇静作用有关。 乙醇对NMDA受体的作用机制尚不清楚 理解，尽管有人提出乙醇与 NMDA受体/通道复合体上的甘氨酸调节位点。此外, 不同镇静/催眠药物行为效应的关系 药物对谷氨酸受体的作用还不是很清楚。 最后，乙醇对谷氨酸受体作用的相对效力 不同的中枢神经系统区域尚未得到充分的描述。因此， 有待检验的假设是：1)乙醇抑制NMDA受体- 通过与甘氨酸调节位点的相互作用或 对NMDA受体的功能很重要的其他部位；2)其他 镇静/催眠剂和乙醇类化合物在以下方面与乙醇不同 它们对谷氨酸受体介导作用的效力和选择性 反应；3)乙醇改变NMDA激活的单个离子的功能 4)乙醇具有不同的效力和选择性 抑制不同中枢神经系统神经元的NMDA受体介导的反应 地区。检验这些假说的实验将使用 神经元全细胞和单通道膜片钳记录技术 来自哺乳动物的中枢神经系统。检测乙醇与乙醇相互作用的实验 NMDA受体上的调节位点，镇静/催眠药和 乙醇类化合物及乙醇对单个NMDA受体门控的作用 将在胎鼠海马神经元中进行离子通道 在细胞培养中生长。检测区域差异的实验 乙醇作用的效力和选择性将在大脑中进行 老鼠的切片。 越来越多的证据表明，酒精对NMDA受体的抑制- 中介反应会导致急性中毒。建议数 实验将有助于我们了解分子机制(S) 乙醇对NMDA受体功能的影响。此外，这些 实验将揭示中枢神经系统的哪些区域受此影响最大 乙醇的抑制作用。希望这些活动的结果 实验将为开发治疗方法提供基础 可以抵消酒精的一些醉人效应。

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.