The Neurotrophic Factor GDNF and Alcohol Addiction

神经营养因子 GDNF 和酒精成瘾

• 批准号: 7217537
• 负责人: DORIT RON
• 金额: $ 37.46万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217537
• 关键词: Acute; Address; Affect; Alcohol consumption; Alcohol dependence; Alcohols; Alkaloids; Antibodies; Attenuated; Behavior; Behavioral; Biochemical; Cells; Chronic; Cocaine; Cultured Cells; Development; Dose; Ethanol; Exposure to; Gene Expression; Goals; Growth Factor; Ibogaine; In Vitro; Infusion procedures; Injection of therapeutic agent; Lead; Mediating; Membrane Microdomains; Messenger RNA; Microinjections; Midbrain structure; Modeling; Molecular; Mus; Mutant Strains Mice; Nerve Growth Factor Receptors; Neuroglia; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Prevention; Property; Protein Tyrosine Kinase; Proteins; Rattus; Receptor Protein-Tyrosine Kinases; Relapse; Research Personnel; Rodent; Role; Self Administration; Self-Administered; Signal Transduction; Site; Slice; Synapses; System; Techniques; Testing; Thinking; Time; Training; Transgenic Mice; Tyrosine; Ventral Tegmental Area; Work; addiction; alcohol effect; alcohol exposure; alcohol response; alcohol seeking behavior; base; chronic alcohol ingestion; dopaminergic neuron; drug of abuse; glycerol dialkyl nonitol tetraethyl ether; in vivo; in vivo Model; neuroadaptation; neurotrophic factor; novel; novel strategies; osmotic minipump; prevent; programs; receptor; research study; response

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.

描述（由申请人提供）：该项目的目的是研究神经胶质衍生的神经营养因子（GDNF）在酒精成瘾中的作用。先前的证据表明，GDNF途径的激活可以逆转生化和行为适应滥用药物。我们发现，天然存在的生物碱ibogaine具有抗羽化特性用于滥用和酒精的药物，可以在体外和体内激活GDNF途径。我们进一步发现，与相应的野生型对照相比，表达GDNF消息的50％的突变小鼠消耗的乙醇更多。奇怪的是，我们还发现细胞急性暴露于GDNF或Ibogaine等乙醇会诱导GDNF受体酪氨酸激酶的磷酸化，而慢性暴露于乙醇会降低RET的蛋白质水平。基于这些结果，我们假设，急性，乙醇将GDNF途径激活为一种稳态途径，以防止或延迟神经照顾的发展，导致成瘾。我们进一步假设，当这种稳态机制停止功能时，长期分子和形态学变化的启动会导致与成瘾发展相关的行为。使用生化和行为方法，该建议将解决这两个假设。在特定的目标1中，我们将测试以下假设：GDNF途径在用乙醇急性治疗细胞或小鼠时激活了GDNF途径，并确定急性乙醇诱导GDNF受体RET磷酸化的机制。在特定目标2中，我们将检验以下假设：长期乙醇治疗抑制了GDNF途径，我们将确定这种抑制作用的生化后果。在特定的目标3中，我们将测试以下假设：GDNF途径的激活将减少，而GDNF途径的抑制作用将增强乙醇在乙醇自我给药和复发模型中的增强活性。我们的长期目标是了解生长因素（例如GDNF）在酒精成瘾中的功能。这些研究产生的信息可能会阐明新的途径，以延迟或预防慢性酒精适应，并可能导致开发用于治疗酒精成瘾的新方法。