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: 3802012
• 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/3802012
• 关键词: NMDA receptors; aspartate; barbiturates; brain cell; calcium channel; calcium channel blockers; calcium flux; cerebellum; ethanol; flurazepam; glycine receptors; magnesium; 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.

乙醇生产的一种潜在机制 典型的中枢神经系统（CNS）抑郁症是通过 抑制兴奋性传递。 谷氨酸含量最多 中枢神经系统中存在兴奋性神经递质。 因此，我们检查了 乙醇对谷氨酸介导的初级传播的影响 小脑神经元培养物。 乙醇是一种有效且有选择性的 谷氨酸对 NMDA 受体亚型作用的抑制剂，以及 对这些细胞中的红藻氨酸受体效果较差。 定义 乙醇在 NMDA 受体上的作用位点，相互作用 对乙醇与几种受体功能调节剂进行了检查。 乙醇诱导抑制 NMDA 刺激的钙内流 具有苯环己哌啶 (PCP) 或镁抑制作用的添加剂 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，甘氨酸的作用是士的宁- 不敏感位点以增强对 NMDA 的反应，并已被建议 是 NMDA 受体的共激动剂，被发现在高浓度下， 逆转乙醇诱导的 NMDA 刺激的钙吸收抑制。 结构-活性研究表明，其他氨基酸 甘氨酸位点的激动剂也能逆转乙醇的抑制作用。 数据 表明乙醇可能会干扰协同行动 NMDA 受体上的谷氨酸和甘氨酸。 的特异性 通过比较巴比妥类药物的作用来研究乙醇的作用 和苯二氮卓类药物。 巴比妥类药物能更有效地抑制 红藻氨酸比 NMDA 刺激钙流入，而氟西泮没有 影响。 兴奋性氨基药物作用的差异特征 酸受体可能有助于特定的药理作用 这些药物。