CHRONIC ETHANOL NEUROTOXICITY AND LONGTERM POTENTIATION

慢性乙醇神经毒性和长期增强作用

• 批准号: 2045321
• 负责人: BRUCE E HUNTER
• 金额: $ 15.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2045321
• 关键词: NMDA receptors; action potentials; afferent nerve; alcoholism /alcohol abuse; aminoacid transport; autoradiography; calcium binding protein; calcium flux; calmodulin dependent protein kinase; electrophysiology; ethanol; gene expression; glutamate receptor; hippocampus; immunocytochemistry; in situ hybridization; laboratory rat; memory disorders; microelectrodes; neural plasticity; neural transmission; neurochemistry; neurotoxins; neurotransmitter metabolism; nontherapeutic iontophoresis; protein kinase; receptor binding; synapses

Chronic ethanol abuse results in brain damage and neuronal dysfunction. Studies in laboratory animals have provided convincing evidence of the specificity of ethanol in inducing this neuronal dysfunction. Nevertheless, we still know little regarding the mechanisms underlying ethanol neurotoxicity nor the morphological or functional basis of the mnemonic deficits associated with chronic ethanol abuse. A major objective of this proposal is to begin to characterize the nature and mechanisms underlying the mnemonic deficit resulting from ethanol neurotoxicity. Chronic ethanol treatment has been shown to result in significant loss of hippocampal neurons, altered dendritic structure and function of surviving neurons and loss or rearrangement of synaptic connections. Long-term potentiation is now considered to be a significant physiological mechanism whereby the hippocampus and other brain regions encode or index experimental representations and evidence indicates that chronic ethanol treatment may profoundly alter the properties of long-term potentiation in the hippocampus. A major objective of this proposal is to characterize the manner in which chronic ethanol treatment disrupts long-term potentiation in the hippocampus using extracellular and intracellular physiological recording techniques. We also propose to begin to characterize the nature of the mechanisms whereby chronic ethanol treatment disrupts long-term potentiation. A considerable amount is known regarding the induction of long-term potentiation in the hippocampus. The induction of long-term potentiation requires activation of an n-methyl-d-aspartate (NMDA) receptor complex which leads to a calcium transient localized to restricted locations in the postsynaptic membrane. This calcium transient likely leads to a specific activation of one or more calcium-sensitive enzyme systems. This molecular cascade in some way results in an increase in the strength of synaptic transmission which can last for hours to days. A major hypothesis to be investigated in this proposal is that chronic ethanol treatment disrupts long-term potentiation through a mechanism that includes alterations in one or more of the steps involved in this molecular cascade. Our studies will focus upon basic chronic ethanol actions upon glutamatesynaptic transmission, intracellular calcium regulatory processes and protein kinase activity. We will utilize electrophysiological, biochemical, autoradiographic and immunocytochemical techniques as well as studies of gene expression to characterize the manner in which chronic ethanol treatment disrupts the induction of long-term potentiation. In view of corollary evidence indicating a role for glutamate synapses and intracellular calcium regulation in excitotoxicity in a variety of disease states, the results of our studies may also have more global implications for the mechanisms whereby ethanol produces neuronal toxicity and dysfunction.

慢性乙醇滥用会导致脑损伤和神经元功能障碍。 实验动物的研究提供了令人信服的证据 乙醇在诱导这种神经元功能障碍时的特异性。 尽管如此，我们仍然对基本机制知之甚少 乙醇神经毒性或形态或功能基础 与慢性乙醇滥用相关的疯率缺陷。 一个主要目标 该提议的内容是开始表征性质和机制 乙醇神经毒性导致的助记肌缺陷的根本。 已显示慢性乙醇治疗可显着丧失 海马神经元，树突状结构改变和幸存的功能 神经元以及突触连接的损失或重排。 长期 现在，增强被认为是重要的生理机制 海马和其他大脑区域编码或索引 实验表示和证据表明慢性乙醇 治疗可能会深刻改变长期增强的特性 海马。 该提议的主要目的是表征 慢性乙醇治疗破坏长期增强的方式 在海马中使用细胞外和细胞内生理 记录技术。 我们还建议开始描述性质 慢性乙醇治疗的机制会破坏长期 增强。 有关诱导的已知 海马的长期增强。 长期归纳 增强需要激活N-甲基-D-天冬氨酸（NMDA）受体 复合物导致钙短暂的局部定位于受限 突触后膜中的位置。 该钙瞬态可能 导致一种或多种对钙敏感酶的特异性激活 系统。 这种分子级联在某种程度上导致 突触传播的强度可以持续数小时至几天。 一个 该提议中要研究的主要假设是慢性 乙醇处理通过一种机制破坏了长期增强 包括在该分子中涉及的一个或多个步骤中的改变 级联。 我们的研究将侧重于基本的慢性乙醇行动 谷氨酸突触，细胞内钙调节过程 和蛋白激酶活性。 我们将利用电生理学， 生化，自显影和免疫细胞化学技术以及 基因表达的研究以表征慢性的方式 乙醇处理破坏了长期增强的诱导。 在 表达谷氨酸突触作用的必然证据的观点和 各种疾病中兴奋性毒性中的细胞内钙调节 国家，我们的研究结果也可能具有更大的全球影响 对于乙醇产生神经元毒性的机制和 功能障碍。