Behavioral and molecular analysis of individual variation of ethanol drinking

描述（由申请人提供）：酒精中毒是一种复杂的多基因疾病，影响大脑中的许多神经递质通路。许多人喝酒，但很少有过度饮酒的倾向。遗传和环境因素都是导致酗酒的原因。据估计，遗传因素导致了大约一半的过度饮酒。我们实验室和其他实验室的研究发现，在啮齿类动物模型中，乙醇自我给药的个体差异持续存在。在实验室模型中，这些乙醇摄入量和偏好的差异可能受到社会压力的影响，因为从属或被打败的动物比具有攻击性的、占主导地位的动物增加了它们的乙醇消耗量。近亲繁殖的老鼠，基因几乎相同，在饮酒行为上也表现出这种个体差异。我们的实验使用一种近亲繁殖的小鼠品系来“箝制”遗传因素，使我们能够研究社会压力对乙醇饮用行为个体差异的影响。我们的假设是，社会压力会在大脑中引起长期的信号变化，从而影响酒精的饮用。

DESCRIPTION (provided by applicant): Alcoholism is a complex, polygenic disease affecting many neurotransmitter pathways in the brain. Many people drink alcohol, but relatively few develop the tendency to drink excessively. Both genetic and environmental factors contribute to this development of alcohol abuse. It has been estimated that genetics contributes to about half of the vulnerability to drink excessively. Studies in our laboratory and others have found persistent individual variability in rodent models of ethanol self-administration. These differences in ethanol intake and preference, in a laboratory model, may be affected by social stress since subordinate or defeated animals increase their ethanol consumption as compared to their aggressive, dominant counterparts. Inbred strains of mice, which are virtually genetically identical, have also shown such individual variation in drinking behaviors. Our experiments use an inbred mouse strain to "clamp" the genetic factors allowing us to study the effects of social stress on the individual variation of ethanol drinking behavior. It is our hypothesis that social stress causes long-lasting signaling changes in the brain that influence ethanol drinking. The proposed study uses a two-pronged approach, behavioral (two-bottle choice drinking, social stress and anxiety measurements) and molecular (DMA microarrays) assays to identify the gene networks affecting ethanol drinking behavior. Experiments will utilize a within and between subjects design. The goals of these experiments are: 1) to characterize a model of social stress in mice; 2) to identify the effects of social stress and anxiety on ethanol drinking; and 3) to identify the gene networks involved in both individual variation of drinking and the effects of social stress on the variation of drinking behavior. Using the proposed model to investigate the non-genetic factors involved in excessive alcohol drinking, we may identify novel therapeutic targets for treating alcohol abuse and alcoholism.