ADENYLYL CYCLASE TRANSGENIC MICE AND ALCOHOLISM

说明：cAMP信号转导系统可能发挥重要作用 在酒精sm的发展中。这项研究的长期目标是 两方面：1)阐明潜在的分子和细胞机制 乙醇对中枢cAMP信号通路的影响 系统，以及2)确定cAMP信号通路所起的作用 在对酒精滥用的生理和行为反应中。如果发生了变化 在cAMP信号是酒精表型的决定因素之一，它 可以想象，动物体内cAMP信号系统的变化 模型可能会改变动物对乙醇的反应。假设是 被评估的是动物对乙醇的反应可以通过 腺酰环化酶(AC)表达的修饰。 为了验证这一假设，过度表达III型AC(AC7： 酒精最敏感的异构体)和缺乏表达的基因敲除小鼠 将生成AC7的。一旦AC7的表达发生变化， 经证实，酒精对突变体大脑中AC活性的敏感性 将对老鼠进行检查。乙醇对油烟发火率的影响 突变小鼠的小脑浦肯野神经元将通过 电生理记录。突变小鼠对急性呼吸道感染的敏感性 酒精中毒将通过测量损失的持续时间来检查 翻正反射(睡眠时间)与体温变化 (体温降低)。突变小鼠慢性耐受性的研究进展 用乙醇处理后，将通过测量 乙醇的催眠和降温作用。体育运动的发展 突变小鼠对乙醇的依赖性将通过评估 酒精戒断后处理所致惊厥的强度。这个 拟议中的研究将产生有价值的酒精中毒动物模型 研究。这些动物还将用于广泛的 与cAMP信号转导有关的生理和行为研究。 拟议的研究还将提供关键的信息，以 确定cAMP信号异常是否是决定因素之一 有酗酒表型的。

DESCRIPTION: The cAMP signal transduction system may play an important role in the development of alcohol sm. The long-term goal of this research is twofold: 1) To elucidate the molecular and cellular mechanisms underlying ethanol's effects on the cAMP signaling pathway in the central nervous system, and 2) To determine the role that the cAMP signaling pathway plays in the physiological and behavioral responses to alcohol abuse. If a change in cAMP signaling is one of the determinants of an alcoholic phenotype, it is conceivable that alterations in the cAMP signaling system in an animal model may change the animal's response to ethanol. The hypothesis to be evaluated is that the response of animals to ethanol can be altered by the modification of adenylyl cyclase (AC) expression. To test this hypothesis, transgenic mice that overexpress type VII AC (AC7: the most ethanol sensitive isoform) and knockout mice that lack expression of AC7 will be generated. Once changes in the expression of AC7 are confirmed, the ethanol sensitivity of AC activity in the brain of the mutant mice will be examined. Ethanol's effect on the firing rate of the cerebellar Purkinje neurons of the mutant mice will be examined by electrophysiological recording. The sensitivity of the mutant mice to acute ethanol intoxication will be examined by measuring the duration of loss of righting reflex (sleep time) and the changes in body temperature (hypothermia). The development of tolerance in the mutant mice chronically treated with ethanol will be examined by measuring the decrease in the hypnotic and hypothermic effects of ethanol. The development of physical dependence in the mutant mice to ethanol will be examined by assessing the intensity of handling-induced convulsions after ethanol withdrawal. The proposed studies will generate valuable animal models for alcoholism research. These animals will also be useful for a wide-range of physiological and behavioral research dealing with cAMP signal transduction. The proposed studies will also provide information critical to the determination of whether abnormal cAMP signaling is one of the determinants of an alcoholic phenotype.