ELECTROPHYSIOLOGY OF ETHANOL-GABA INTERACTIONS

对乙醇的行为敏感性是一个复杂的特征，似乎 取决于许多不同的基因，这些基因都有助于 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 确定行为差异的细胞基础。一种机制 我们假设这是行为乙醇的重要决定因素 敏感性是我们在电中观察到的急性神经元耐受性 生理实验，在 5-7 分钟内达到最大 甲醇的应用，并且发生得足够快，以至于这种类型的 甚至在血液乙醇浓度达到之前就可能出现耐受性 达到了他们的巅峰水平。我们已经观察到这种形式的宽容 选择性培育乙醇敏感性动物的单细胞水平 （短睡眠小鼠和低酒精敏感性大鼠），但不适用于动物 选择增加乙醇敏感性（长睡眠小鼠和高 酒精敏感性大鼠）。我们建议比较这个非常快速的阶段 大脑区域（海马和小脑）之间以及其他区域之间的耐受性 专门为快速反应而选择的小鼠品系 获得行为乙醇耐受性。我们还建议确定 是否存在可以解释行为的细胞机制 急性功能耐受现象，其发展较慢（ 超过 30 分钟），并且没有电生理相关性 已被识别。第二系列实验将检查同类 分离个体数量性状基因座（QTL）的小鼠 对乙醇不敏感的短睡眠或乙醇对乙醇的敏感性 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差异相关 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，以及是否 存在与急性差异相关的单独且不同的 QTL 神经元耐受性和初始敏感性。最后一组实验 将检查细胞水平上 GABA 反应的差异 过度表达 gamma2L 或 gamma2S 的转基因小鼠品系 GABAa 受体的亚基，假设它发挥作用 该受体对乙醇的敏感性。

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.