Biochemical and Genetic Determinants of Differences in Alcohol Consumption

描述（由申请人提供）：该INIA资助的总体目标是定义酒精回避机制，并为其他INIA研究人员提供行为测试方面的专业知识，以评估新突变小鼠的乙醇相关行为。根据我们从INIA资助的当前时期的数据，我们提出啮齿动物避免高浓度乙醇是由肝脏和大脑中促炎细胞因子的释放和/或产生增加引起的，并且这些细胞因子引起大脑中基因表达的长期变化。我们还发现，当酒精持续存在时，对酒精的初始高接受度会降低，每周禁欲期，这种降低取决于遗传背景。我们开发了两种遗传小鼠模型，它们保持一致的高水平的偏好和消费（FVBxB 6 F1小鼠;持续的酒精偏好，SAP）或发展避免酒精（NZBxB 6 F1小鼠;减少的酒精偏好，RAP）。这些动物模型提供了机会，比较大脑基因表达谱形成的初始饮酒，持续消费和发展的酒精避免。为了验证细胞因子假说，我们将研究：1）缺乏某些促炎细胞因子和/或其受体基因的基因敲除小鼠的乙醇消耗; 2）促炎细胞因子全身治疗的效果（特别是α-TNF）和细胞因子受体拮抗剂对自愿乙醇消耗的影响; 3）细胞因子处理后的脑基因表达谱，以允许与从具有乙醇回避的小鼠获得的阵列数据进行比较; 4）通过3个循环的饮酒和戒酒处理FVBxB 6 F1和NZBxB 6 F1杂交小鼠，并通过微阵列分析鉴定关键基因; 5）通过施用RNAi产生关键基因的脑区域敲低小鼠。这项工作将使用3个INIA核心（德克萨斯阵列和信息学核心，RA Harris -PI;科罗拉多RNAi核心，W. Zawada - PI;加州小鼠动物模型核心，A.罗伯茨- PI）和合作，与六个INIA研究人员（A。Alcantara -德克萨斯州奥斯汀; S.德克萨斯州奥斯汀; R. D.梅菲尔德-奥斯汀，得克萨斯州; R.戴维斯-休斯顿，德克萨斯州; A.里亚比宁-波特兰，俄勒冈州; B。Tabakoff - Aurora，科罗拉多）。

DESCRIPTION (provided by applicant): The overall objective of this INIA grant is to define mechanisms of alcohol avoidance and provide expertise in behavioral testing to other INIA investigators to evaluate ethanol-related behaviors in new mutant mice. Based on our data from the current period of INIA funding, we propose that the avoidance of high concentrations of ethanol by rodents is caused by increased release and/or production of proinflammatory cytokines in liver and brain and that these cytokines cause long-lasting changes in gene expression in the brain. We also found that initial high acceptance of alcohol can decrease when alcohol is presented continuously with intervening weekly abstinence periods, and this decrease depends upon the genetic background. We developed two genetic mouse models which maintain consistent high levels of preference and consumption (FVBxB6F1 mice; Sustained Alcohol Preference, SAP) or develop avoidance of alcohol (NZBxB6F1 mice; Reduced Alcohol Preference, RAP). These animal models provide the opportunity to compare brain gene expression profiles formed by initial alcohol consumption, sustained consumption and development of alcohol avoidance. To test the cytokine hypothesis, we will study: 1) ethanol consumption in knockout mice lacking genes for some proinflammatory cytokines and/or their receptors; 2) the effect of systemic treatment with proinflammatory cytokines (particularly a-TNF) and antagonists of cytokine receptors on voluntary ethanol consumption; 3) brain gene expression profiles after cytokine treatment to allow comparison with array data obtained from mice with ethanol avoidance; 4) treatment of FVBxB6F1 and NZBxB6F1 hybrid mice via 3 cycles of alcohol consumption and abstinence and identification of key genes by microarray analysis; 5) generation of brain regional knock-down mice of key genes by administration of RNAi. This work will use 3 INIA Cores (Texas Array and Informatics Core, RA Harris -PI; Colorado RNAi core, W. Zawada - PI; California Mouse Animal Model Core, A. Roberts - PI) and collaborations with six INIA investigators (A. Alcantara - Austin, Texas; S. Bergeson - Austin, Texas; R. D. Mayfield - Austin, Texas; R. Davis - Houston, Texas; A. Ryabinin - Portland, Oregon; B. Tabakoff - Aurora, Colorado).