BDNF and Alcohol Addiction

描述（由申请人提供）：我们的长期目标是测试内源性系统抵消酒精的不良作用并预防或延迟酒精成瘾的发展的假设。我们进一步假设，这些途径的功能障碍增加了酒精中毒的易感性。该假设基于我们最近的研究，该研究证明了一种稳态脑源性神经营养因子（BDNF）介导的信号传导途径，该途径通过急性和间歇性暴露于中等浓度的乙醇（在切片和体内）而上调，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的表达，特别是在背侧纹状体，一个控制习惯学习的大脑区域，BDNF基因的整体减少或BDNF通路的抑制增加了乙醇饮酒行为[3，8]。使用分子和行为的方法相结合，我们计划：1）确定是否内源性背侧纹状体BDNF及其下游效应器，多巴胺D3受体和神经肽，强啡肽，是一个调节机制的一部分，控制动机消耗乙醇在大鼠。2)测试BDNF基因中的单核苷酸多态性是否已被证明会损害BDNF功能，并与人类各种精神疾病和成瘾的风险增加有关，导致背侧纹状体中这种保护途径的破坏，并增加小鼠对乙醇不良作用的敏感性。3)确定长期暴露于过量乙醇是否与离体和体内BDNF通路的抑制有关。酒精中毒是一种毁灭性的疾病，表现为不受控制的饮酒。因此，了解控制这种表型的分子机制具有很大的意义，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风险因素。这项提议旨在确定BDNF及其下游效应物多巴胺D3受体和神经肽强啡肽是否是内源性“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，发生在这种保护途径下调时，和/或BDNF基因突变时。酒精依赖是我们社会中普遍存在的问题，尽管经过数十年的研究，但治疗这种疾病的药物很少。从这项研究中产生的结果可能会导致药物开发的新目标，以治疗酒精中毒和识别疾病的遗传风险因素的识别。

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.