BDNF and Alcohol Addiction

描述(由申请者提供)：我们的长期目标是测试内源性系统抵消酒精不良反应的假设，防止或延缓酒精成瘾的发展。我们进一步假设，这些通路的故障增加了酒精中毒的易感性。这一假说是基于我们最近的研究，该研究证明了一种由脑源性神经营养因子(BDNF)介导的信号通路，该通路在切片和体内急性和间歇性暴露于中等浓度的乙醇后上调，并抑制小鼠对乙醇的敏感性[3，8]。例如，我们观察到，小鼠自愿饮酒增加了BDNF在背侧纹状体的表达，背侧纹状体是控制习惯学习的大脑区域，BDNF基因的整体减少或BDNF途径的抑制增加了饮酒行为[3，8]。利用分子和行为相结合的方法，我们计划：1)确定内源性背侧纹状体BDNF及其下游效应物多巴胺D3受体和神经肽强啡肽是否是控制大鼠饮酒动机的调节机制的一部分。2)测试BDNF基因中的单核苷酸多态是否导致背侧纹状体的这一保护途径的破坏，并增加小鼠对乙醇不良反应的敏感性。BDNF基因的单核苷酸多态已被证明削弱BDNF的功能，并与人类患各种精神疾病和成瘾的风险增加有关。3)确定长期暴露于过量乙醇是否与体内和体外BDNF途径的抑制有关。酗酒是一种毁灭性的疾病，表现为无节制的饮酒。因此，了解控制这种表型的分子机制是非常有意义的，可能会导致识别治疗酒精中毒的药物开发的新靶点，并可能导致识别疾病的遗传危险因素。这项建议旨在确定BDNF及其下游效应物--多巴胺D3受体和神经肽强啡肽--是否属于内源性“抗成瘾”级联反应的一部分。我们的假设进一步表明，导致成瘾表型的行为适应，如强迫性饮酒，发生在这一保护途径下调时，和/或BDNF基因突变时。酒精依赖在我们的社会中是一个普遍的问题，尽管有几十年的研究，但治疗这种疾病的药物很少。这项研究产生的结果可能导致确定治疗酒精中毒的药物开发的新靶点，并确定该疾病的遗传风险因素。

DESCRIPTION (provided by applicant): Our long-term goal is to test the hypothesis that endogenous systems counteract the adverse actions of alcohol and prevent or delay the development of alcohol addiction. We further hypothesize that malfunction of such pathways increases susceptibility for the development of alcoholism. This hypothesis is based on our recent studies demonstrating a homeostatic brain-derived neurotrophic factor (BDNF)-mediated signaling pathway that is upregulated by acute and intermittent exposure to moderate concentrations of ethanol, both in slices and in vivo, and suppresses sensitivity of mice to ethanol [3, 8]. For example, we observed that voluntary ethanol consumption in mice increases the expression of BDNF specifically in the dorsal striatum, a brain region that controls habit learning, and global reduction of the BDNF gene or inhibition of the BDNF pathway increases ethanol-drinking behaviors [3, 8]. Using a combination of molecular and behavioral approaches, we plan to: 1) Determine whether endogenous dorsal striatal BDNF and its downstream effectors, the dopamine D3 receptor and the neuropeptide, dynorphin, are part of a regulatory mechanism controlling motivation to consume ethanol in rats. 2) Test whether a single nucleotide polymorphism in the BDNF gene that has been shown to impair BDNF function, and is linked to increased risk for various psychiatric disorders and addiction in humans, leads to a breakdown of this protective pathway in the dorsal striatum, and increases sensitivity of mice to the adverse actions of ethanol. 3) Determine whether chronic exposure to excessive levels of ethanol is associated with the inhibition of the BDNF pathway ex vivo and in vivo. Alcoholism is a devastating disease that manifests itself as uncontrolled drinking. Understanding the molecular mechanisms that control this phenotype are therefore of great interest and will likely lead to the identification of new targets for medication development to treat alcoholism, and may lead to the identification of genetic risk factors for the disease. This proposal is aimed to determine whether BDNF and its down-stream effectors, the dopamine D3 receptor and the neuropeptide Dynorphin, are part of an endogenous "anti-addiction" cascade. Our hypothesis further suggests that behavioral adaptations that result in addictive phenotypes, such as compulsive alcohol consumption, occur when this protective pathway is down-regulated, and/or when the BDNF gene is mutated. Alcohol dependence is a widespread problem in our society, and despite decades of research, very few medications exist to treat the disease. Results generated from this study could lead to the identification of new targets for medication development to treat alcoholism and to the identification of genetic risk factors for the disease.