The Neurotrophic Factor GDNF and Alcohol Addiction

描述(申请人提供)：本项目的目标是研究胶质源性神经营养因子(GDNF)在酒精成瘾中的作用。先前的证据表明，GDNF通路的激活可以逆转对滥用药物的生化和行为适应。我们发现，天然存在的生物碱伊波甘具有抗滥用药物和酒精成瘾的特性，在体外和体内都激活了GDNF途径。我们进一步发现，表达50%GDNF消息的突变小鼠比它们相应的野生型对照小鼠消耗更多的乙醇。奇怪的是，我们还发现，细胞急性暴露于乙醇，如GDNF或Ibogaine，会诱导GDNF受体酪氨酸激酶Ret的磷酸化，而长期暴露于乙醇会降低Ret的蛋白水平。基于这些结果，我们假设，乙醇强烈地激活了GDNF途径，作为一种动态平衡途径，防止或延迟导致成瘾的神经适应的发展。我们进一步假设，当这种动态平衡机制停止运作时，就会启动长期的分子和形态变化，导致与成瘾发展相关的行为。通过使用生化和行为学方法，这项提议将解决这两种假设。在具体目标1中，我们将检验乙醇急性处理细胞或小鼠时GDNF途径被激活的假设，并确定急性乙醇诱导GDNF受体Ret磷酸化的机制。在特定的目标2中，我们将检验长期乙醇处理抑制GDNF途径的假设，并确定这种抑制的生化后果。在具体目标3中，我们将验证假设，即在乙醇自我给药和复发模型中，GDNF途径的激活将减少，而GDNF途径的抑制将增强乙醇的增强活性。我们的长期目标是了解GDNF等生长因子在酒精成瘾中的作用。这些研究产生的信息可能阐明延缓或防止对慢性酒精适应的新途径，并可能导致开发治疗酒精成瘾的新方法。

DESCRIPTION (provided by applicant): The goal of this project is to study the role of the glial derived neurotrophic factor (GDNF) in alcohol addiction. Previous evidence suggests that activation of the GDNF pathway can reverse biochemical and behavioral adaptations to drugs of abuse. We found that the naturally occurring alkaloid Ibogaine, that possesses anti-addiction properties for drugs of abuse and alcohol, activates the GDNF pathway in vitro and in vivo. We further found that mutant mice that express 50% of the GDNF message consume more ethanol than their corresponding wild-type controls. Curiously, we also found that acute exposure of cells to ethanol, like GDNF or Ibogaine, induces the phosphorylation of the GDNF receptor tyrosine kinase, Ret, whereas chronic exposure to ethanol reduces the protein level of Ret. Based on these results we hypothesize that, acutely, ethanol activates the GDNF pathway as a homeostatic pathway that prevents or delays the development of neuroadaptations leading to addiction. We further hypothesize that when this homeostatic mechanism ceases functioning, the initiation of long-term molecular and morphological changes that lead to behaviors associated with the development of addiction occur. Using biochemical and behavioral approaches, this proposal will address both hypotheses. In specific aim 1, we will test the hypothesis that the GDNF pathway is activated upon acute treatment of cells or mice with ethanol, and identify the mechanism by which acute ethanol induces the phosphorylation of the GDNF receptor Ret. In specific aim 2, we will test the hypothesis that long-term ethanol treatment inhibits the GDNF pathway and we will identify the biochemical consequences of this inhibition. In specific aim 3, we will test the hypothesis that activation of the GDNF pathway will reduce whereas inhibition of the GDNF pathway will enhance the reinforcing activities of ethanol in ethanol self-administration and relapse models. Our long-term goal is understand the function of growth factors such as GDNF in alcohol addiction. The information generated from these studies may elucidate novel pathways for the delay or prevention of adaptations to chronic alcohol and may lead to the development of new approaches for the treatment of alcohol addiction.