DJ-1-Dopamine Transporter Interactions in Models of Addiction

DJ-1-多巴胺转运蛋白在成瘾模型中的相互作用

• 批准号: 8234072
• 负责人: Amy Beatrice Manning-Bog
• 金额: $ 9.76万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234072
• 关键词: Acute; Addictive Behavior; Affect; American; Antioxidants; Behavior; Behavioral; Binding; Brain; Cell membrane; Central Nervous System Diseases; Centrifugation; Chronic; Cocaine; Development; Disease; Dopamine; Drug usage; Evaluation; Exposure to; Functional disorder; Genetic Predisposition to Disease; Goals; Health; Impairment; Laboratories; Measures; Mediating; Methamphetamine; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neurodegenerative Disorders; Neurons; Neurotoxins; Nucleus Accumbens; Oxidation-Reduction; PARK7 protein; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Pharmaceutical Preparations; Play; Preparation; Property; Proteins; Regulation; Research; Rewards; Role; Surveys; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Model; Transgenic Organisms; Ventral Tegmental Area; Western Blotting; addiction; behavioral sensitization; cocaine exposure; cocaine use; conditioning; dopamine transporter; drug of abuse; drug seeking behavior; endophenotype; gene environment interaction; insight; mortality; motor impairment; mouse model; neurotransmission; new therapeutic target; nigrostriatal pathway; novel; presynaptic; psychostimulant; public health relevance; radioligand; response; trafficking; uptake

DESCRIPTION (provided by applicant): The long term goal of our research is to elucidate whether DJ-1 and its related pathways represent a convergent mechanism for disorders involving dopaminergic dysfunction. The objectives of this pilot proposal are: (1) to determine whether the Parkinson's disease-associated protein DJ-1 contributes to the molecular mechanisms underlying reward acquisition in the mesolimbic pathway, and (2) whether behaviors in response to psychomotor stimulants are altered in DJ-1-deficient mice. Cellular localization of the dopamine transporter (DAT) regulates dopamine uptake activity and thus represents a target mechanism underlying addiction. Our transgenic mouse model the DJ-1-deficiency demonstrates enhanced presynaptic DAT levels, which leads to increased vulnerability to neurotoxicants in models of Parkinson's disease. No thorough analysis of the impact of DJ-1 and its related mechanisms on dopaminergic neurotransmission in the mesolimbic pathway has been performed. We posit that DJ-1 deficiency likely alters DAT localization and activity in the mesolimbic pathway, and through this mechanism, may contribute to behavioral changes following exposure to drugs of abuse. If our hypotheses are correct, these studies should identify a novel mechanism involved in reward acquisition and provide a new target for therapeutics to counter the addictive effects of drugs of abuse. PUBLIC HEALTH RELEVANCE: Use of cocaine and methamphetamine (METH) contributes to morbidity and mortality in nearly 7 million Americans (2008 National Survey on Drug Use and Health). Currently, few therapeutic options are available to inhibit drug-seeking behaviors. The long-term goal of our research is to delineate novel targets that affect reward responses in the brain. On the path to achieving this goal, we propose to identify new pathological substrates of the mechanisms that contribute to development of addiction, specifically the Parkinson's disease (PD)-related protein DJ-1. Our studies in DJ-1-deficient transgenic mice have revealed alterations in the dopamine transporter (DAT) that contribute to neuronal vulnerability and locomotor impairments in the nigrostriatal pathway. Because DAT is integral to the reward response, we expect that DJ-1 or its related mechanisms may contribute to reward acquisition in models of psychomotor stimulant use.

描述（由申请人提供）：我们研究的长期目标是阐明DJ-1及其相关通路是否代表涉及多巴胺能功能障碍的疾病的会聚机制。该试验性提案的目标是：（1）确定帕金森病相关蛋白DJ-1是否有助于中脑边缘通路中奖励获得的分子机制，以及（2）DJ-1缺陷小鼠对精神兴奋剂的反应行为是否改变。多巴胺转运蛋白（DAT）的细胞定位调节多巴胺摄取活性，因此代表了成瘾的目标机制。我们的转基因小鼠模型DJ-1缺陷表现出增强的突触前DAT水平，这导致帕金森病模型对神经毒物的脆弱性增加。尚未对DJ-1及其相关机制对中脑边缘通路中多巴胺能神经传递的影响进行全面分析。我们认为，DJ-1缺乏可能会改变DAT的定位和活性的中脑边缘通路，并通过这种机制，可能有助于行为的变化后，暴露于滥用药物。如果我们的假设是正确的，这些研究应该确定一个新的机制参与奖励获取，并提供一个新的治疗目标，以对抗滥用药物的成瘾作用。 公共卫生相关性：可卡因和甲基苯丙胺（METH）的使用导致近700万美国人的发病率和死亡率（2008年全国药物使用和健康调查）。目前，很少有治疗选择可用于抑制药物寻求行为。我们研究的长期目标是描绘影响大脑奖励反应的新目标。在实现这一目标的道路上，我们建议确定有助于成瘾发展的机制的新病理底物，特别是帕金森病（PD）相关蛋白DJ-1。我们在DJ-1缺陷型转基因小鼠中的研究揭示了多巴胺转运蛋白（DAT）的改变，这些改变导致黑质纹状体通路中的神经元脆弱性和运动障碍。由于DAT是不可或缺的奖励反应，我们预计，DJ-1或其相关机制可能有助于奖励收购的精神兴奋剂使用模型。