ALCOHOL ACTIONS: A BEHAVIORAL PHARMACOGENETICS APPROACH

药物遗传学是一门旨在阐明 遗传因素对药物反应的个体差异的影响。相关 行为药物遗传学，源于这样一种认识， 对药物的行为反应原则上与 生理或生化反应。这一做法最终导致了 针对急性敏感性差异的啮齿动物品系的遗传选择 乙醇。这些由基因定义的动物种群提供了一个 这是一个有用的工具，用于测试有关生化机制的假设， 是对乙醇的行为敏感性差异的基础。 现在有相当多的证据表明，急性接触乙醇会增强 GABA控制的氯离子通道的开放我们已经证明， 一种技术，允许直接 测量脑膜囊泡中GABA介导的氯离子内流。使用 这项技术，我们发现啮齿动物谁是敏感的， 乙醇行为的影响，也对乙醇诱导的 与乙醇相比，GABA介导的氯离子通量增加 抗性选择对应物。乙醇敏感动物也被发现 对GABA介导的氯离子通量增加更敏感， 苯二氮卓类药物，但对GABA激动剂蝇蕈醇或 戊巴比妥似乎有密切的关系（无论是在体内， 体外）之间的敏感性，乙醇和苯二氮卓类。与此相反， 对这两种药物的敏感性与对 作用于氯离子通道复合物的其它药剂如GABA激动剂， 戊巴比妥或惊厥药拟议的研究将确定以下方面的作用： GABA/苯二氮卓受体氯离子通道复合物的表达 和遗传的乙醇敏感性，使用行为药物遗传学和 经典的孟德尔遗传技术。预计这些 研究将提供深入了解神经和遗传机制 对乙醇敏感。

Pharmacogenetics is a discipline that seeks to elucidate the contribution of genetic factors to individual differences in drug responses. The related discipline, behavioral pharmacogenetics, stems from the realization that behavioral responses to drugs are in principle no different from physiological or biochemical responses. This approach has culminated in genetic selection of lines of rodents for differences in acute sensitivity to ethanol. These genetically defined populations of animals provide a useful tool for testing hypotheses about the biochemical mechanisms that underlie the selected differences in behavioral sensitivity to ethanol. There is now considerable evidence that acute exposure to ethanol enhances the opening of GABA-operated chloride channels. We have demonstrated and pharmacologically characterized a technique that allows for the direct measure of GABA-mediated chloride influx in brain membrane vesicles. Using this technique we have found rodents who are sensitive to the depressant effects of ethanol behaviorally, are also sensitive to ethanol-induced increases in GABA-mediated chloride flux compared to their ethanol resistant selection counterparts. Ethanol sensitive animals were also found more sensitive to augmentation of GABA-mediated chloride flux by benzodiazepires, but not more sensitive to the GABA agonist, muscimol or to pentobarbital. There appears to be a close relationship (both in vivo and in vitro) between sensitivity to ethanol and benzodiazepines. In contrast, sensitivity to these two drugs is not closely -related to sensitivity to other agents acting on the chloride channel complex such as GABA agonists, pentobarbital or convulsants. The proposed research will define the role of the GABA/Benzodiazepine receptor chloride channel complex in the expression and inheritance of ethanol sensitivity using behavioral pharmacogenetic and classical Mendelian genetic techniques. It is anticipated that these studies will provide insight in to the neural and genetic mechanisms responsible for ethanol sensitivity.