ANIMAL GENETICS

描述（由申请人提供）：本5年提案的长期目标是 了解，在遗传易感受试者的中枢神经系统中，由于酒精暴露而发生的复杂神经元改变，这会促进高度饮酒行为和复发。总体假设是，在具有高度饮酒行为遗传倾向的个体中，某些CNS神经元回路易受酒精改变的影响，因此，高度饮酒开始并维持，并促进酒精复发性饮酒。本提案的目标是确定自愿饮酒产生的基因和蛋白质表达的长期变化，这些变化可能与高酒精饮酒和复发有关。这些研究将使用近亲繁殖的成年雄性酒精偏好（iP）、高酒精饮用（iliAD）、酒精非偏好（iNP）和低酒精饮用（iLAD）大鼠。微芯片表达阵列将用于检测基因表达的变化，二维凝胶电泳程序将用于检测蛋白质表达的变化。前两个具体目标将比较iP和 iNP大鼠和复制的iliAD和iLAD大鼠之间的比较，并确定iP和iliAD大鼠自愿饮酒对延髓核、前额叶皮质和后海马基因和蛋白表达变化的影响。第二个2个具体目标将检查操作性口服酒精自我给药、消退训练和恢复对iP和iliAD大鼠这些边缘区中基因和蛋白质表达的影响。这一研究内容与该中心研究酒精摄入遗传决定因素的主题相结合。拟议的项目与以下核心直接互动：行政，动物生产，基因组学和分子生物学，蛋白质组学。这一大鼠遗传组成部分补充了人类遗传学的两个研究组成部分，并与小鼠选择性育种和遗传组成部分科学地相互作用。这一项目的结果将提供关于酒精成瘾的潜在机制的宝贵信息，从而可能导致开发治疗酒精中毒和酒精滥用的药物疗法。

DESCRIPTION (provided by applicant): The long-range goals of this 5-year proposal are to understand, in the CNS of genetically vulnerable subjects, the complex neuronal alterations that occur as a result of alcohol exposure, which promote high alcohol drinking behavior and relapse. The overall hypothesis is that, in individuals with a genetic predis-position for high alcohol drinking behavior, certain CNS neuronal circuits are susceptible to alterations by alcohol and, as a result, high alcohol drinking is initiated and maintained, and alcohol relapse drinking is promoted. The goals of the present proposal are to determine the long-term changes in gene and protein expression produced by voluntary alcohol drinking that may be associated with high alcohol drinking and relapse. Inbred adult male alcohol preferring (iP), high-alcohol-drinking (iliAD), alcohol-non-preferring (iNP) and low-alcohol-drinking (iLAD) rats will be used for these studies. The microchip expression array will be used to examine changes in gene expression, and 2-dimensional gel electrophoresis procedures will be used to examine changes in protein expression. The first 2 specific aims will compare innate differences between iP and iNP rats and between replicate iliAD and iLAD rats, and determine the effects of voluntary alcohol drinking by iP and iliAD rats on changes in gene and protein expression in the nucleus accumbens, prefrontal cortex and posterior hippocampus. The second 2 specific aims will examine the effects of operant oral alcohol self-administration, extinction training and reinstatement on gene and protein expression in these limbic regions of the iP and iliAD rats. This research component integrates well with the Center's theme of studying genetic determinants of alcohol ingestion. The proposed project interacts directly with the following cores: Administrative, Animal Production, Genomics and Molecular Biology, and Proteomics. This rat genetic component complements the 2 research components dealing with Human Genetics, and scientifically interacts with the Mouse Selective Breeding and Genetics Component. The results of this project will provide valuable information on mechanisms underlying alcohol addiction, which could lead to the development of pharmacotherapies for the treatment of alcoholism and alcohol abuse.