ELECTROPHYSIOLOGY OF ETHANOL-GABA INTERACTIONS

对酒精的行为敏感性是一种复杂的特征，似乎 依赖于许多不同的基因，这些基因都对 行为表型。我们将使用电生理技术来研究 乙醇在细胞水平上的作用在已经被 根据对酒精的行为反应进行选择，以便 找出行为差异的细胞基础。一种机制 我们的假设是行为酒精的一个重要决定因素 敏感性是我们在脑电活动中观察到的急性神经元耐受 生理实验，在接下来的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 耐受性甚至可能在血液中乙醇浓度 达到了最高水平。我们观察到了这种形式的容忍 为酒精敏感性而选择性饲养的动物的单细胞水平 (睡眠不足的小鼠和低酒精敏感性的大鼠)，但不是在动物身上 选择用于提高酒精敏感性(长睡眠小鼠和高 酒精敏感大鼠)。我们建议将这一非常快速的阶段 大脑区域(海马体和小脑)之间的耐受性，以及其他 专门为快速选育的小鼠品系 获得行为性酒精耐量。我们还建议确定 是否有细胞机制可以解释行为 急性功能耐受现象，发展较慢( 超过30分钟)，并且没有电生理关联 已经被确认了。第二系列实验将检验同源基因 分离单个数量性状基因座(QTL)的小鼠 对酒精不敏感的短睡眠或酒精敏感性 敏感的长时间睡眠背景。我们假设一些QTL会 与我们之前在 海马区和小脑区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 小脑和海马体对酒精的敏感性，以及 有不同的和不同的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Gamma2L或Gamma2S的转基因小鼠品系 GABAA受体的亚单位，已被假设发挥作用 这种受体对酒精的敏感性。

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.