Behavioral and molecular analysis of individual variation of ethanol drinking

描述(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途径。许多人饮酒，但相对较少的人有过度饮酒的倾向。遗传和环境因素都促成了酒精滥用的发展。据估计，在过度饮酒的易感性中，大约有一半是遗传因素造成的。我们实验室和其他实验室的研究发现，在乙醇自我给药的啮齿动物模型中，个体差异持续存在。在实验室模型中，乙醇摄入量和偏好的这些差异可能会受到社会压力的影响，因为与攻击性的、占主导地位的动物相比，从属或被击败的动物会增加它们的乙醇消耗量。近亲交配的小鼠在饮酒行为上也表现出了这样的个体差异，它们在基因上几乎是相同的。我们的实验使用近亲交配的小鼠品系来“夹住”遗传因素，使我们能够研究社会压力对饮酒行为个体差异的影响。我们的假设是，社会压力会导致大脑中长期持续的信号变化，从而影响饮酒。 这项拟议的研究使用双管齐下的方法，行为(两瓶选择饮酒，社交压力和焦虑测量)和分子(DMA微阵列)分析来确定影响酒精饮酒行为的基因网络。实验将采用受试者内部和受试者之间的设计。这些实验的目的是：1)描述小鼠的社会压力模型；2)确定社会压力和焦虑对饮酒的影响；3)确定与饮酒的个体差异和社会压力对饮酒行为的影响有关的基因网络。利用所提出的模型研究过度饮酒涉及的非遗传因素，我们可能会找到治疗酒精滥用和酒精中毒的新靶点。

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.