ADENYLYL CYCLASE TRANSGENIC MICE AND ALCOHOLISM

说明：cAMP信号转导系统可能在细胞内起重要作用 在酒精SM的发展中。 这项研究的长期目标是 双重：1）阐明其分子和细胞机制 乙醇对中枢神经系统cAMP信号通路的影响 系统，和2）确定cAMP信号通路发挥的作用， 在生理和行为上对酒精滥用的反应。 如果改变 在cAMP信号转导是酒精表型的决定因素之一，它 可以想象，动物中cAMP信号系统的改变 模型可能会改变动物对乙醇的反应。 假设是 评估的是，动物对乙醇的反应可以被改变， 腺苷酸环化酶（AC）表达的修饰。 为了验证这一假设，过表达VII型AC（AC7： 最乙醇敏感的同种型）和缺乏表达的基因敲除小鼠 AC7将被生成。 一旦AC7的表达发生变化， 证实，突变体脑中AC活性的乙醇敏感性 将对小鼠进行检查。 乙醇对燃烧速率的影响 将通过以下方法检查突变小鼠的小脑浦肯野神经元： 电生理记录 突变小鼠对急性 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）和体温变化 （体温过低）。 突变小鼠慢性耐受性的形成 将通过测量用乙醇处理的样品中 催眠和降低体温作用。 发展有形 通过评估突变小鼠对乙醇的依赖性， 乙醇戒断后处理诱导惊厥的强度。 的 拟议中的研究将产生有价值的酒精中毒动物模型 research. 这些动物也将有助于广泛的 cAMP信号转导的生理和行为研究。 拟议的研究还将提供关键信息， 确定异常cAMP信号传导是否是决定性因素之一 酒精中毒的表现

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.