Biochemical and Genetic Determinants of Differences in Alcohol Consumption

描述（由申请人提供）：这项INIA资助的总体目标是确定酒精避免的机制，并为其他INIA研究者提供行为测试方面的专业知识，以评估新突变小鼠的酒精相关行为。根据我们目前在INIA资助期间的数据，我们提出啮齿动物对高浓度乙醇的回避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，这些细胞因子导致大脑中基因表达的长期变化。我们还发现，在每周戒酒期间持续饮酒时，最初对酒精的高度接受度会下降，这种下降取决于遗传背景。我们建立了两种遗传小鼠模型，它们保持一致的高水平偏好和消费（FVBxB6F1小鼠；持续酒精偏好，SAP）或产生酒精回避（NZBxB6F1小鼠；减少酒精偏好，RAP）。这些动物模型提供了比较最初饮酒、持续饮酒和戒酒形成的大脑基因表达谱的机会。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/或其受体基因的敲除小鼠的乙醇消耗量；2)用促炎细胞因子（特别是a-TNF）和细胞因子受体拮抗剂进行全身治疗对自愿酒精消耗的影响；3)细胞因子处理后的大脑基因表达谱，以便与乙醇回避小鼠的阵列数据进行比较；4)对FVBxB6F1和NZBxB6F1杂交小鼠进行3个周期的饮酒和戒酒治疗，并通过微阵列分析鉴定关键基因；5)用RNAi诱导关键基因的脑区域敲低小鼠的产生。这项工作将使用3个INIA核心（Texas Array and Informatics Core, RA Harris -PI; Colorado RNAi Core， W. Zawada -PI; California Mouse Animal Model Core， A. Roberts -PI），并与6名INIA研究者（A. Alcantara - Austin, Texas； S. Bergeson - Austin, Texas； R. Mayfield - Austin, Texas； R. Davis - Houston, Texas； A. Ryabinin - Portland, Oregon； B. Tabakoff - Aurora, Colorado）合作。

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).