Drugs of abuse, Dopamine and the Circadian Clock: a Metabolomic Study

描述（由申请人提供）：昼夜节律支配着大量的生理、生化和行为反应，其中断可能导致抑郁、失眠、双相情感障碍和其他精神疾病。最近的证据表明，生物钟和新陈代谢之间有着密切的联系。虽然滥用药物扰乱昼夜节律是有据可查的，但尚不清楚这是如何发生的，以及滥用药物对细胞代谢的影响有多深远。这一应用的智力价值是在分子水平上破译和解释了一系列有趣的观察结果，这些观察结果表明，滥用药物引起的多巴胺能系统功能障碍与昼夜节律的破坏有关。多巴胺是成瘾过程中的关键分子。多巴胺还调节运动和激素活动，并在控制动机和情绪行为方面发挥主导作用。本申请集中在多巴胺能系统的一个主要元素，多巴胺D2受体（D2R）。D2R是控制细胞和行为反应的关键参与者，这些反应调节运动功能、大脑奖赏回路和内分泌控制。有趣的是，这些功能也是以昼夜节律的方式调节的。我们实验室收集的结果揭示了D2R介导的信号传导和昼夜节律机制控制之间的分子联系。该应用程序高度集中于解决一个具有广泛生物学意义的问题： 多巴胺介导的信号传导、生物钟和药物滥用之间的因果关系。我们创新的质谱方法加上最先进的生物计算，将首次破译参与时钟控制和对滥用药物做出反应的大脑区域的代谢组图。这一应用除了具有高度针对性外，还具有更广泛的影响，因为它解决了一个具有根本重要性的概念问题。事实上，拟议中的研究将产生的成果很可能分支走向令人兴奋的新途径，包括其他领域的研究。因此，这个项目很可能是一个有价值的门户，更广泛的研究领域的代谢和表观遗传事件在神经元反应中所发挥的作用，与开放的新途径，治疗干预脑疾病的影响。拟议研究的结果将在未来的方向发展，包括在各种动物模型中对各种滥用药物进行比较代谢组学分析。

DESCRIPTION (provided by applicant): Circadian rhythms dominate a large array of physiological, biochemical and behavioral responses and their disruption may lead to depression, insomnia, bipolar disorders and other mental illnesses. Recent evidence demonstrates intimate links between the circadian clock and metabolism. While it is well documented that drugs of abuse disrupt circadian rhythms, it is still unclear how this may happen and how profound is the influence of drugs of abuse on cellular metabolism. The intellectual merit of this application is to decipher and interpret at the molecular level a seriesof fascinating observations showing that dysfunctions of the dopaminergic system, induced by drugs of abuse, are associated with disruption of the circadian rhythms. Dopamine is a key molecule in the process of addiction. Dopamine also regulates motor and hormonal activities, and has a leading role in controlling motivated and emotional behaviors. This application is focused on one principal element of the dopaminergic system, the dopamine D2 receptor (D2R). D2Rs are key players in the control of the cellular and behavioral responses that regulate motor function, brain reward circuitries and endocrine control. Intriguingly, these functions are also modulated in a circadian manner. Results gathered in our laboratories have revealed a molecular link between D2R-mediated signaling and control of the circadian machinery. This application is highly focused to solve a question of broad biological significance: deciphering the causal link between dopamine-mediated signalling, the circadian clock and drugs of abuse. Our innovative mass-spectrometry approach coupled with state-of-the-art biocomputing, will decipher, for the first time, the metabolome map of brain areas involved in clock control and in response to drugs of abuse. The application, in addition of being highly targeted, has much broader impact as it tackles a conceptual question of basic importance. Indeed, the proposed research will generate outcomes that are likely to branch towards exciting new avenues that embrace additional fields of research. It is thereby highly likely that this project constitutes a valuable gateway to the broader field of study related to the role played by metabolic and epigenetic events in neuronal responses, with implications of opening novel avenues for therapeutic intervention in brain disorders. The outcome of the proposed research will develop in future directions including a comparative metabolome analysis of various drugs of abuse in various animal models.