Biochemical and Genetic Determinants of Differences in Alcohol Consumption

INIA赠款的总体目标是确定避免饮酒的机制并提供专门知识 在行为测试中，其他INIA研究人员评估新突变小鼠的酒精相关行为。 根据我们从INIA本期资金中获得的数据，我们建议避免高额 啮齿类动物酒精浓度的增加是由促炎物质的释放和/或产生增加引起的 肝和脑中的细胞因子，以及这些细胞因子引起的基因表达的长期变化 大脑。我们还发现，当提供酒精时，最初对酒精的高度接受度会降低 持续每周一次的间歇性禁欲，这种减少取决于基因 背景资料。我们开发了两种保持一致的高偏好水平的遗传小鼠模型 和饮酒(FVBxB6F1小鼠；持续性酒精偏好，SAP)或出现避免饮酒 (NZBxB6F1小鼠；降低酒精偏好，RAP)。这些动物模型提供了一个机会 比较首次饮酒、持续饮酒和持续饮酒所形成的脑基因表达谱 避免饮酒的发展。为了验证细胞因子假说，我们将研究：1)乙醇消费在 缺乏某些促炎细胞因子和/或其受体基因的基因敲除小鼠；2) 促炎症细胞因子(尤其是α-肿瘤坏死因子)和细胞因子受体拮抗剂的全身治疗 自愿饮酒；3)细胞因子治疗后的脑基因表达谱 4)FVBxB6F1和 NZBxB6F1杂交鼠3个周期饮酒戒酒及关键基因的鉴定 通过基因芯片分析；5)通过给药产生脑区域关键基因敲除小鼠 RNAi。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；科罗拉多州RNAi Core，W.Zawada-Pi；加利福尼亚小鼠动物模型核心，A.Roberts-Pi)以及与六个 INIA调查人员(A.Alcantara-奥斯汀，德克萨斯州；S.Bergeson-奥斯汀；R.D.Mayfield-奥斯汀， 德克萨斯州；R.Davis--德克萨斯州休斯顿；A.Ryabinin--俄勒冈州波特兰；B.Tabakoff-Aurora，科罗拉多州)。

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).