ELECTROPHYSIOLOGY OF ETHANOL-GABA INTERACTIONS

乙醇-GABA 相互作用的电生理学

• 批准号: 6299166
• 负责人: THOMAS V DUNWIDDIE
• 金额: $ 15万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299166
• 关键词: GABA receptor; beta adrenergic receptor; beta adrenergic receptor kinase; biological models; cerebellum; cerebral cortex; drug tolerance; electrophysiology; ethanol; genetic models; hippocampus; laboratory mouse; laboratory rat; lateral olfactory area; medial olfactory area; neural transmission; neuropharmacology; norepinephrine; protein kinase A; protein kinase C; receptor expression; receptor sensitivity

Behavioral sensitivity to ethanol is a complex trait that appears to depend upon a number of different genes that all contribute to the behavioral phenotype. We will use electrophysiological techniques to study the actions of ethanol at the cellular level in animals that have been selected on the basis of behavioral responses to ethanol, in order to identify the cellular bases for differences in behavior. One mechanism that we hypothesize is an important determinant of behavioral ethanol sensitivity is the acute neuronal tolerance that we observe in electro- physiological experiments, which is maximal within 5-7 minutes following methanol application, and occurs rapidly enough that this type of tolerance could occur even before blood ethanol concentrations have reached their peak levels. We have observed this form of tolerance at the single cell level in animals selectively bred for ethanol sensitivity (short sleep mice and low alcohol sensitivity rats), but not in animals selected for increased ethanol sensitivity (long sleep mice and high alcohol sensitivity rats). We propose to compare this very rapid phase of tolerance between brain regions (hippocampus and cerebellum), and in other lines of mice that have been selected specifically for the rapid acquisition of behavioral ethanol tolerance. We also propose to determine whether there are cellular mechanisms that can account for the behavioral phenomenon of acute functional tolerance, which develops more slowly ( greater than 30 minutes), and for which no electrophysiological correlates have been identified. A second series of experiments will examine congenic mice that isolate individual quantitative trait loci (QTLs) for behavioral sensitivity to ethanol on a ethanol insensitive short sleep or ethanol sensitive long sleep background. We hypothesize that some of the QTLs will be associated with differences that we have previously observed in electrophysiological responses to ethanol in hippocampus and cerebellum. We will determine whether the same QTL-associated genes control initial ethanol sensitivity in the cerebellum and in the hippocampus, and whether there are separate and distinct QTLs associated with differences in acute neuronal tolerance and initial sensitivity. A final set of experiments will examine differences in GABAergic responses at the cellular level in lines of transgenic mice that overexpress either the gamma2L or gamma2S subunit of the GABAa receptor, which has been hypothesized to play a role in the ethanol sensitivity of this receptor.

对乙醇的行为敏感性是一个复杂的特征， 依赖于许多不同的基因， 行为表型我们将使用电生理技术来研究 乙醇在动物细胞水平上的作用， 根据对乙醇的行为反应进行选择，以便 识别行为差异的细胞基础。一种机制 我们假设这是行为酒精的重要决定因素 敏感性是我们在电刺激中观察到的急性神经耐受性， 生理实验，这是最大的5-7分钟后， 甲醇的应用，并发生足够迅速，这种类型的 甚至在血液中乙醇浓度 达到了他们的巅峰水平。我们已经观察到这种形式的宽容， 在针对乙醇敏感性选择性饲养的动物中的单细胞水平 （短睡眠小鼠和低酒精敏感性大鼠），但不是在动物中 选择增加的乙醇敏感性（长睡眠小鼠和高睡眠小鼠）， 酒精敏感大鼠）。我们建议将这一非常快速的阶段 大脑区域（海马和小脑）之间的耐受性，以及其他 小鼠品系，这些品系是专门为快速 获得行为乙醇耐受性。我们还建议确定 是否有细胞机制可以解释 急性功能性耐受现象，其发展较慢（ 大于30分钟），并且与电生理学无关 已被确认。第二组实验将检查同源基因 小鼠分离个体数量性状基因座（QTL）， 对乙醇不敏感的短暂睡眠或乙醇 敏感的长时间睡眠背景。我们假设一些QTL将 与我们之前观察到的 海马和小脑对乙醇的电生理反应。 我们将确定是否相同的QTL相关基因控制初始 小脑和海马的乙醇敏感性，以及 存在独立且不同的QTL与急性 神经元耐受性和初始敏感性。最后一组实验 将在细胞水平上研究GABA能反应的差异， 过表达γ 2L或γ 2S的转基因小鼠品系 GABAa受体的亚基，这已被假设发挥作用， 对乙醇的敏感性。