EFFECTS OF ETHANOL ON NMDA-MEDIATED NEURONAL FUNCTION

乙醇对 NMDA 介导的神经元功能的影响

• 批准号: 3808694
• 负责人: C S RABE
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3808694
• 关键词: NMDA receptors; aspartate; barbiturates; brain cell; calcium channel; calcium channel blockers; calcium flux; calcium metabolism; cerebellum; ethanol; flurazepam; glutamate receptor; glycine receptors; ionophores; magnesium; membrane channels; metabolism; neural transmission; neurons; neurotransmitter metabolism; phencyclidine; tissue /cell culture

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.

乙醇可能产生其特性的一种潜在机制 中枢神经系统（CNS）抑制是通过抑制兴奋性来实现的 传播。谷氨酸是最丰富的兴奋性神经递质 存在于中枢神经系统中。因此，我们研究了乙醇对 小脑神经元原代培养物中谷氨酸介导的传递。 乙醇是谷氨酸作用的有效和选择性抑制剂 NMDA 受体亚型，对红藻氨酸受体效果较差 在这些细胞中。确定乙醇在 NMDA 的作用位点 受体，乙醇与受体的几种调节剂的相互作用 功能进行了检查。乙醇诱导的 NMDA 刺激抑制 钙流入与苯环己哌啶 (PCP) 产生的抑制作用相加 或镁离子，表明乙醇不作用于该位点内 受体门控离子通道。乙醇也不会改变 NMDA 的 EC(50) 刺激钙吸收，表明与钙没有直接相互作用 NMDA 结合位点。然而，甘氨酸对士的宁不敏感。 网站以增强响应 NMDA，并被认为是 NMDA 受体的共激动剂， 发现，在高浓度下，可以逆转乙醇诱导的抑制作用 NMDA 刺激钙吸收。结构-活性研究表明 在甘氨酸位点充当激动剂的其他氨基酸也发生逆转 乙醇抑制。数据表明乙醇可能会干扰 谷氨酸和甘氨酸对 NMDA 受体的协同作用。这 通过比较乙醇作用的特异性来研究 巴比妥类药物和苯二氮卓类药物。巴比妥类药物更有效 抑制红藻氨酸比 NMDA 刺激的钙内流，而氟西泮 没有效果。兴奋性氨基药物作用的差异特征 酸受体可能有助于这些药物的特定药理作用 药物。