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，但相对较少的人会过度饮酒。遗传和环境因素都有助于酒精滥用的发展。据估计，遗传因素造成了大约一半的酗酒问题。在我们实验室和其他研究中发现，在乙醇自我给药的啮齿动物模型中存在持续的个体差异。在实验室模型中，乙醇摄入量和偏好的这些差异可能受到社会压力的影响，因为与具有攻击性的占主导地位的动物相比，从属或被击败的动物增加了乙醇消耗量。近亲繁殖的小鼠品系在遗传上几乎是相同的，它们在饮酒行为上也表现出了这种个体差异。我们的实验使用近交系小鼠品系来“钳制”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，社会压力会导致大脑中影响乙醇饮用的长期信号变化。 这项研究采用了双管齐下的方法，行为（两瓶选择饮酒，社会压力和焦虑测量）和分子（DMA微阵列）测定，以确定影响乙醇饮酒行为的基因网络。实验将采用受试者内和受试者间设计。这些实验的目的是：1）表征小鼠的社会应激模型; 2）确定社会应激和焦虑对乙醇饮酒的影响; 3）确定参与饮酒个体差异和社会应激对饮酒行为差异影响的基因网络。使用所提出的模型来调查过度饮酒的非遗传因素，我们可能会发现新的治疗酒精滥用和酒精中毒的治疗目标。

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.