EFFECTS OF ETHANOL ON NMDA-MEDIATED NEURONAL FUNCTION

一种潜在的机制，乙醇可能会产生其 典型的中枢神经系统（CNS）抑郁症是通过 抑制兴奋性传递。 谷氨酸是最丰富的 中枢神经系统中的兴奋性神经递质。 因此，我们检查了 乙醇对原发性肝癌谷氨酸介导的传递的影响 小脑神经元的培养物。 乙醇是一种有效的选择性 谷氨酸对NMDA受体亚型作用的抑制剂，和 对这些细胞中的红藻氨酸受体的作用较小。 以限定 乙醇在NMDA受体上的作用位点， 检测了具有几种受体功能调节剂的乙醇。 乙醇诱导的抑制NMDA刺激的钙内流是 具有苯环己哌啶（PCP）或镁产生的抑制作用的添加剂 离子，表明乙醇不作用于受体内的位点- 门控离子通道 乙醇也没有改变NMDA的EC/50 刺激钙摄取，表明与 NMDA结合位点。 然而，甘氨酸，作用于士的宁- 不敏感位点，以增强对NMDA的反应，并已建议， 是NMDA受体的共激动剂，发现，在高浓度下， 逆转乙醇诱导的NMDA刺激的钙摄取抑制。 结构-活性研究表明，其他氨基酸，作为 甘氨酸位点的激动剂也逆转乙醇抑制。 数据 这表明乙醇可能会干扰 谷氨酸盐和甘氨酸在NMDA受体。 的特异性 通过比较巴比妥类药物的作用，研究了乙醇的作用 和苯二氮卓类。 巴比妥类药物在抑制 红藻氨酸比NMDA刺激的钙内流，而氟安定没有 效果 兴奋性氨基酸的药物效应差异 酸受体可能有助于特定的药理作用， 这些药物。

One potential mechanism by which ethanol might produce its characteristic central nervous system (CNS) depression is through inhibition of excitatory transmission. Glutamate is the most abundant excitatory neurotransmitter present in the CNS. Therefore, we examined the effect of ethanol on glutamate-mediated transmission in primary cultures of cerebellar neurons. Ethanol was a potent and selective inhibitor of the actions of glutamate at the NMDA receptor subtype, and was less effective at the kainate receptor in these cells. To define the site of action of ethanol at the NMDA receptor, interactions of ethanol with several modulators of receptor function were examined. Ethanol-induced inhibition of NMDA-stimulated calcium influx was additive with inhibition produced by phencyclidine (PCP) or magnesium ion, indicating that ethanol does not act at a site within the receptor- gated ion channel. Ethanol also did not alter the EC/50 for NMDA stimulation of calcium uptake, suggesting no direct interaction with the NMDA binding site. However, glycine, which acts at a strychnine- insensitive site to enhance responses to NMDA, and has been suggested to be a co-agonist at the NMDA receptor, was found, at high concentrations, to reverse ethanol-induced inhibition of NMDA-stimulated calcium uptake. Structure-activity studies showed that other amino acids that act as agonists at the glycine site also reversed ethanol inhibition. The data suggest that ethanol may interfere with the concerted actions of glutamate and glycine at the NMDA receptor. The specificity of ethanol's action was investigated by comparing effects of barbiturates and benzodiazepines. Barbiturates were more effective at inhibiting kainate- than NMDA-stimulated calcium influx, while flurazepam had no effect. The differential profile of drug effects at excitatory amino acid receptors may contribute to specific pharmacological actions of these drugs.