DJ-1-Dopamine Transporter Interactions in Models of Addiction

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了涉及多巴胺能功能障碍的疾病的汇聚机制。这个试点方案的目的是：(1)确定帕金森氏病相关蛋白DJ-1是否有助于中脑边缘通路中奖赏获得的分子机制，以及(2)在DJ-1缺陷小鼠中，对精神运动刺激剂的反应是否发生改变。多巴胺转运体(DAT)的细胞定位调节多巴胺摄取活性，从而代表成瘾的靶机制。我们的转基因小鼠模型DJ-1缺乏显示出突触前DAT水平增强，这导致帕金森病模型中对神经毒物的易感性增加。DJ-1在中脑边缘通路中对多巴胺能神经传递的影响及其相关机制还没有得到彻底的分析。我们推测DJ-1缺乏可能改变了DAT在中脑边缘通路中的定位和活性，并通过这一机制可能有助于药物滥用后的行为变化。如果我们的假设是正确的，这些研究应该确定一种涉及奖励获得的新机制，并为治疗学提供一个新的靶点，以对抗滥用药物的成瘾效应。 公共卫生相关性：可卡因和甲基苯丙胺(冰毒)的使用导致近700万美国人的发病率和死亡率(2008年全国药物使用与健康调查)。目前，几乎没有可用的治疗选择来抑制药物寻求行为。我们研究的长期目标是描绘出影响大脑奖赏反应的新目标。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新的病理底物，特别是帕金森氏病(PD)相关蛋白DJ-1。我们对DJ-1基因缺陷转基因小鼠的研究揭示了多巴胺转运体(DAT)的变化，这种变化导致黑质纹状体通路中神经元的脆弱性和运动障碍。由于DAT是奖赏反应的组成部分，我们预计DJ-1或其相关机制可能有助于精神运动刺激剂使用模型中的奖赏获得。

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.