The Neurotrophic Factor GDNF and Alcohol Addiction

项目描述：本项目的目的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替尼，具有抗成瘾性质的药物滥用和酒精，激活GDNF途径在体外和体内。我们进一步发现，表达50% GDNF信息的突变小鼠比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，急性暴露于乙醇的细胞，如GDNF或伊波替尼，诱导GDNF受体酪氨酸激酶Ret的磷酸化，而慢性暴露于乙醇降低了Ret的蛋白水平。基于这些结果，我们假设，急性，乙醇激活GDNF通路作为一种稳态通路，防止或延迟神经适应的发展，导致成瘾。我们进一步假设，当这种自我平衡机制停止运作时，会引发长期的分子和形态学变化，导致与成瘾发展相关的行为。使用生物化学和行为的方法，这个建议将解决这两个假设。在具体目标1中，我们将检验GDNF通路在用乙醇急性处理细胞或小鼠后被激活的假设，并鉴定急性乙醇诱导GDNF受体Ret磷酸化的机制。在具体目标2中，我们将检验长期乙醇处理抑制GDNF通路的假设，并确定这种抑制的生化后果。在具体的目标3中，我们将检验以下假设：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生长因子如GDNF在酒精成瘾中的作用。从这些研究中产生的信息可能会阐明新的途径，延迟或预防适应慢性酒精，并可能导致开发新的方法治疗酒精成瘾。

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.