The Neurotrophic Factor GDNF and Alcohol Addiction

描述（由申请人提供）：我们的长期目标是验证生长因子，如神经胶质细胞系衍生的神经营养因子（GDNF）抵消酒精的不良作用，从而预防或延缓酒精成瘾的发展的假设。在第一轮资助中，我们发现中脑多巴胺能腹侧被盖区（VTA） GDNF通路的激活迅速减弱了乙醇消费的动机和复发。采用多学科的方法，我们计划阐明GDNF减少乙醇消耗的作用机制。在目的1中，我们将研究VTA中的GDNF是否具有内在的奖励或刺激特性。在Aim 2中，我们将确定GDNF是否在长期过量乙醇消耗的大鼠模型中调节VTA神经元的兴奋性。在目标3中，我们将测试VTA中的GDNF是否会改变过量乙醇消耗导致的伏隔核多巴胺水平的神经适应性。在Aim 4中，我们将阐明GDNF减轻酒精饮酒行为的分子机制。酗酒是一种毁灭性的疾病，表现为不受控制的酗酒。因此，识别抑制这种表型的信号通路，例如由GDNF激活的信号通路，是非常有趣的，因为这可能会导致识别治疗酒精中毒的药物开发的新靶点，也可能导致识别该疾病的遗传风险因素。公共卫生相关性：酗酒是一种毁灭性的疾病，仅在美国每年就影响大约1400万人。不幸的是，目前只有有限数量的药物被FDA批准用于治疗与该疾病相关的不良表型。因此，迫切需要确定药物开发的新靶点。我们发现生长因子GDNF是饮酒行为和复发的负调节因子。因此，GDNF及其下游效应蛋白是治疗酒精中毒的潜在药物靶点。在这里，我们计划阐明GDNF调节酒精作用的机制。从这些研究中产生的结果可能导致开发新的、选择性的药物来治疗酒精滥用。

DESCRIPTION (provided by applicant): Our long-term goal is to test the hypothesis that growth factors such as the glial cell line-derived neurotrophic factor (GDNF) counteract the adverse actions of alcohol and thus prevent or delay the development of alcohol addiction. In the first round of funding we found that the activation of the GDNF pathway in the midbrain dopaminergic ventral tegmental area (VTA) rapidly attenuates the motivation for, and relapse to, ethanol consumption. Using a multidisciplinary approach, we plan to elucidate the mechanism underlying the actions of GDNF to reduce consumption of ethanol. In Aim 1, we will examine whether GDNF in the VTA possesses intrinsic rewarding or stimulant properties. In Aim 2, we will determine whether GDNF adjusts the excitability of VTA neurons in a rat model of long-term excessive ethanol consumption. In Aim 3 we will test if GDNF in the VTA modifies the neuroadaptations in dopamine levels in the nucleus accumbens resulting from excessive ethanol consumption. In Aim 4, we will elucidate the molecular mechanism responsible for GDNF's action to attenuate ethanol-drinking behaviors. Alcoholism is a devastating disease that manifests itself in uncontrolled consumption. Identifying signaling pathways that inhibit this phenotype, such as the ones activated by GDNF, are therefore of great interest, as this will likely lead to the identification of new targets for medication development to treat alcoholism, and may also lead to the identification of genetic risk factors for the disease. PUBLIC HEALTH RELEVANCE: Alcoholism is a devastating disease that affects approximately 14 million people per year in the USA alone. Unfortunately, only limited numbers of drugs are currently approved by the FDA to treat adverse phenotypes associated with the disease. Therefore, there is a great need to identify novel targets for medication development. We found that the growth factor GDNF is a negative regulator of alcohol-drinking behaviors and relapse. Therefore, GDNF and its downstream effector proteins are potential drug targets to treat alcoholism. Here, we plan to elucidate the mechanism by which GDNF regulates alcohol's actions. Results generated from these studies may lead to development of novel, selective agents to treat alcohol abuse.