GENETIC APPROACHES TO NEUROPHARMACOLOGY OF ETHANOL

这个项目的目标是发现分子机制。 给予酒精的遗传性行为差异 无论是人还是动物。在这个过程中，我们学到了很多关于 乙醇对中枢神经系统的作用机制 井。长期目标是为 确定那些处于发展风险中的个体 以及为预防和治疗酒精中毒提供依据 乙醇的急性和慢性影响。这些技术依赖于 大量使用动物作为人类的遗传基因。近交系 异源群体、选系、重组自交系 使用的是老鼠和大鼠。通过使用选择性的技术 在动物上进行育种已经有可能培育出这两个品系 小鼠和大鼠在中枢神经系统的敏感性上存在很大差异 给神经系统注射初始剂量的乙醇。重组自交系 来自小鼠品系的动物是为了不同的初始 将提供敏感度(短睡眠SS和长睡眠LS) 进行详细的基因分析。家鼠的选育 同样的目的也在一个独立的项目中进行。有选择性的 对戒断敏感性的繁殖已经产生了将 允许我们进行同样类型的详细的遗传和 我们已经完成的戒断的分子分析 初始敏感度问题。党卫军的大脑分析 和LS小鼠，通过神经药理学技术， 神经生理学、神经化学、酶学和蛋白质化学 已经让我们决定集中精力在即将到来的时期 乙醇的分子作用与γ-氨基丁酸的关系 氯离子通道机制及细胞内钙离子的作用 在乙醇的急性作用中。 关于将研究结果外推到人类的初步研究 动物对急性敏感度和急性耐受性的发展 人类已经接近完成了。在接下来的时期里，我们将 启动一个新项目，研究人类对恭维的退缩 我们对选定小鼠品系的戒断机制进行了研究。

The goals of this project are to discover the molecular mechanisms of the inherited behavioral differences to administered ethanol in both man and animals. In this process much is learned about the mechanisms of ethanol's action on the central nervous system as well. The long-term objective is to provide a rational basis for the identification of those individuals at risk of developing alcoholism as well as to provide for the prevention and treatment of ethanol's acute and chronic effects. The techniques rely heavily upon the use of animal as human genetics. Inbred strains heterogenous stocks, selected lines, recombinant inbred strain-of mice and rats are used. By the use of the technique of selective breeding in animals it has been possible to develop lines of both mice and rats that differ widely in the sensitivity of the central nervous system to an initial dose of ethanol. Recombinant inbred animals from the mouse lines bred for differences in initial sensitivity (short sleep SS and long sleep LS) will be available for detailed genetic analysis. Selective breeding of rats for the same purpose is proceeding in an independent project. Selective breeding for withdrawal sensitivity has produced mice that will allow us to carry out the same type of detailed genetic and molecular analysis of withdrawal that we have accomplished with problems of initial sensitivity. Analysis of the brains of the SS and LS mice by the techniques of neuropharmacology, neurophysiology, neurochemistry, enzymology and protein chemistry has let us to the decision to concentrate in the upcoming period on the molecular actions of ethanol with relationship to the GABA- chloride channel mechanisms and the role of intracellular calcium in the acute actions of ethanol. Initial studies on the extrapolation to humans of the findings with animals on acute sensitivity and development of acute tolerance to humans has nearly been completed. In the upcoming period we will start a new project in study of withdrawal in humans to compliment our studies of withdrawal mechanism in selected lines of mice.