Excessive Alcohol Intake Induced By Withdrawal

到目前为止，现有的遗传动物模型并不能不受控制地自我管理酒精。目前的建议将使用遗传和环境操作相结合的方法来证明戒断引起的过量酒精摄入，目的是生产一种动物模型，以便容易地出口到INIA内外的其他实验室。这些数据将提供给INIA的信息学核心，以建议分子研究（基因阵列核心）以及生理研究（神经回路亚组和成像核心）的目标。该项目还将广泛使用遗传动物模型核心。与Specific Aim 1相关的研究将提供关于存在高乙醇消耗基因型以及这些动物是否会摄入中毒剂量乙醇的重要信息。与特异性目标2相关的研究将为选择性育种目标（即特异性目标3）中使用的最佳范例提供关键的背景信息，其目标是产生一个或多个可靠的过度饮酒遗传动物模型。该模型在对选择反应不重要的基因上应该是相当稳定的（即，漂变应该最小化），并且将生成实验的重复以消除对遗传相关性的假阳性估计。由于我们建议为过量饮酒产生2-3个独立的重复系，因此直接选择和相关反应之间的任何相似性都将为表型的遗传共决定提供非常有力的证据。由于将测试额外的遗传动物模型以及来自其他INIA位点的基因型，因此与Specific Aim 4相关的研究将更清楚地了解戒断相关基因和偏好相关基因对过量酒精摄入表型的作用。总的来说，拟议的研究将解决我们联盟的长期目标，即确定过量饮酒表型的神经生物学机制。这些信息不仅有助于我们进一步了解酒精摄入和戒断之间的相互作用，而且还有助于制定治疗酒精中毒的新策略。

To date, existing genetic animal models do not self-administer alcohol uncontrollably. The present proposal will use a combination of genetic and environmental manipulations to demonstrate excessive alcohol intake induced by withdrawal with the goal of producing an animal model that is easily exported to other laboratories within and beyond the INIA. The data will be made available to the Informatics Core of the INIA to suggest targets for molecular studies (Gene Array Core) as well as physiological studies (Neurocircuitry subgroup and Imaging Core). This project also will make extensive use of the Genetic Animal Models Core. Studies related to Specific Aim 1 will provide important information on the existence of genotypes with high ethanol consumption and whether these animals consume intoxicating doses of ethanol. Studies related to Specific Aim 2 will provide critical background information for an optimal paradigm to be used in the selective breeding aim (i.e., Specific Aim 3), the goal of which is to produce one or more reliable genetic animal model(s) of excessive drinking. The model should be genetically fairly stable at genes not important for the selection response (i.e., drift should be minimized) and replications of the experiment will be generated to eliminate false- positive estimates of genetic correlation. Since we are proposing to produce 2-3 independent replicate lines for excessive alcohol intake, any parallelism between the directly selected and correlated responses will offer very strong evidence for genetic codetermination of the phenotype. The studies related to Specific Aim 4 will give a clearer idea of the role of withdrawal-related and preference-related genes to the excessive alcohol intake phenotype, since additional genetic animal models as well as genotypes from other INIA sites will be tested. Collectively, the proposed studies will address a long term goal of our consortium which is to determine the neurobiological mechanisms underlying the excessive alcohol intake phenotype. Not only will this information help in furthering our understanding of the interaction between ethanol intake and withdrawal, but it also would aid in the development of new strategies for the treatment of alcoholism.