EXCITOTOXIC AMINO ACID RECEPTORS IN BRAINS OF ALCOHOLICS

酗酒者大脑中的兴奋性毒性氨基酸受体

• 批准号: 2045482
• 负责人: GERHARD FREUND
• 金额: $ 9.73万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-01 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2045482
• 关键词: NMDA receptors; alcoholism /alcohol abuse; autoradiography; cerebellum; frontal lobe /cortex; glutamate receptor; glutamates; glycine; hippocampus; histology; human tissue; ligands; membrane channels; nervous system disorder; neuroanatomy; neurons; temporal lobe /cortex

Chronic exposure to alcohol results in the loss of neurons in human brain by an as yet undetermined mechanism. We hypothesize that alterations in excitatory amino acid (EAA) receptors are central to the neuropathology associated with chronic exposure to alcohol and that by understanding these changes rational treatments can be developed. Acute exposure to alcohol inhibits N-methyl-D-aspartate (NMDA) receptors. More prolonged exposure results in compensatory upregulation which may sensitize neurons to excitotoxicity during withdrawal. Such cycles repeated over a lifetime may eventually result in losses of neurons bearing EEA receptors. We propose to test this hypothesis by measuring EAA receptors in brains of alcoholics and non-alcoholic controls available in our brain bank which currently contains over 150 brains. These brains are well characterized as to cause of death, alcohol consumption history, postmortem delay, medications, and premortem agonal states. Each brain has been examined histologically and found to be free of significant pathology unrelated to alcoholism. This information is stored in a computer data base and will be used for various analyses to determine effects of various pre- and post-mortem conditions other than alcoholism that may affect EAA receptors. We will concentrate on brain regions known to be affected by alcohol abuse, eg frontal cortex, temporal cortex, hippocampus and cerebellum. Specific aims are to investigate: 1) The binding of ligands to agonist, antagonist, ion-channel and glycine sites on the NMDA-receptor and associated ion channel; determination of the effects of glutamate and glycine on NMDA receptor channel opening-kinetics and effects of in vitro ethanol on these parameters. 2) Determine if alcoholics have altered AMPA and kainate receptor densities and/or affinities. 3) Determine the relationship between density of receptors and density of neurons by quantitative autoradiography and histological examination. These investigations will conclusively determine if changes in excitotoxic amino acid receptors are associated with neuropathology known to occur in chronic alcoholism.

长期接触酒精会导致人脑神经元丢失 是由一种尚未确定的机制造成的 我们假设， 兴奋性氨基酸（EAA）受体是神经病理学的中心 与长期酒精接触有关， 这些变化可以制定合理的治疗方法。 急性暴露于 酒精抑制N-甲基-D-天冬氨酸（NMDA）受体。 更长 暴露导致补偿性上调， 兴奋性中毒的症状 这样的循环在一个 寿命可能最终导致携带EEA的神经元的损失 受体。 我们建议通过测量EAA受体来验证这一假设 在酗酒者和非酗酒者的大脑中 目前拥有超过150个大脑。 这些大脑 死因饮酒史 死后延迟用药和死前濒死状态 每个大脑 已进行组织学检查，发现无显著 病理学与酗酒无关 此信息存储在 计算机数据库，并将用于各种分析，以确定 除了酒精中毒之外， 可能会影响EAA受体。 我们将集中在大脑区域 已知受酒精滥用影响，如额叶皮层、颞叶 皮质海马和小脑 具体目标是调查：1） 配体与激动剂、拮抗剂、离子通道和甘氨酸的结合 NMDA受体和相关离子通道上的位点; 谷氨酸和甘氨酸对NMDA受体通道的影响 开放动力学和体外乙醇对这些参数的影响。（二） 确定酗酒者是否改变了AMPA和红藻氨酸受体密度 和/或亲和力。3)确定密度之间的关系 受体和神经元密度的定量放射自显影， 组织学检查 这些调查将最终确定 确定兴奋性毒性氨基酸受体的变化是否与 患有慢性酒精中毒的神经病变