Excessive Alcohol Intake Induced By Withdrawal

到目前为止，现有的遗传动物模型不会不受控制地自我管理酒精。本提案将使用遗传和环境操作的组合来证明戒断引起的过量酒精摄入，目的是生产一种易于出口到INIA内外其他实验室的动物模型。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。与特定目标1相关的研究将提供关于高乙醇消耗基因型存在的重要信息，以及这些动物是否消耗了致醉剂量的乙醇。与特定目标2相关的研究将为选择性育种目标中使用的最佳范例提供关键的背景信息（即，具体目标3），其目标是产生一个或多个可靠的过量饮酒的遗传动物模型。该模型在对选择反应不重要的基因上应该是遗传上相当稳定的（即，漂移应最小化），并将产生实验的重复以消除遗传相关性的假阳性估计。由于我们建议生产2 - 3个独立的重复线过量饮酒，直接选择和相关的反应之间的任何平行性将提供非常强有力的证据遗传共同决定的表型。与特定目标4相关的研究将更清楚地了解戒断相关和偏好相关基因对过量酒精摄入表型的作用，因为将测试其他遗传动物模型以及来自其他INIA位点的基因型。总的来说，拟议的研究将解决我们联盟的长期目标，即确定过量酒精摄入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，而且还有助于开发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.