Biochemical and Genetic Determinants of Differences in Alcohol Consumption

这项INIA赠款的总体目标是确定避免饮酒的机制并提供专业知识 在行为测试中，其他INIA研究人员评估了新突变小鼠的乙醇相关行为。 根据我们从INIA资助的当前阶段获得的数据，我们建议避免高风险。 啮齿动物的乙醇浓度是由促炎性物质的释放和/或产生增加引起的。 这些细胞因子引起肝脏和大脑中基因表达的长期变化， 个脑袋我们还发现，当出现酒精时，最初对酒精的高接受度会降低 连续与干预每周禁欲期，这种减少取决于遗传 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偏好， 和消耗（FVBxB 6 F1小鼠;持续酒精偏好，SAP）或避免酒精 （NZBxB 6 F1小鼠;酒精偏好降低，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酒精消费，持续消费， 避免酒精的发展。为了检验细胞因子假说，我们将研究：1）在哺乳动物中的乙醇消耗， 缺乏某些促炎细胞因子和/或其受体基因的敲除小鼠; 2） 用促炎细胞因子（特别是α-TNF）和细胞因子受体拮抗剂的全身治疗 3）细胞因子治疗后的脑基因表达谱， 与从具有乙醇回避的小鼠获得的阵列数据的比较; 4）FVBxB 6 F1和 NZBxB 6 F1杂交小鼠经3个周期的饮酒和戒断及关键基因的鉴定 通过微阵列分析; 5）通过施用 RNA干扰这项工作将使用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. Roberts - PI）以及与六位 INIA调查员（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， 德克萨斯州; 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）。

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)andcollaborations withsix 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).