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

滥用药物、多巴胺和昼夜节律时钟：代谢组学研究

• 批准号: 8534521
• 负责人: Emiliana Borrelli
• 金额: $ 30.78万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534521
• 关键词: Acute; Animal Model; Area; Behavior; Behavioral; Biochemical; Biocompatible Materials; Biological; Bipolar Disorder; Brain; Brain Diseases; Brain Mapping; Brain region; Cells; Circadian Rhythms; Clinical Research; Cocaine; Communities; Corpus striatum structure; Coupled; Data; Dopamine; Dopamine D2 Receptor; Drug Controls; Drug abuse; Elements; Emotional; Endocrine; Epigenetic Process; Event; Functional disorder; Future; Gene Expression Profile; Genotype; Goals; Hormonal; Human; Imagery; Investigation; Knock-out; Knowledge; Laboratories; Lead; Link; Maps; Mass Spectrum Analysis; Mediating; Mental Depression; Mental disorders; Metabolic; Metabolic Pathway; Metabolism; Molecular; Motor; Mus; Mutant Strains Mice; Neurons; Neurosecretory Systems; Nucleus Accumbens; Outcome; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Play; Positioning Attribute; Process; Protocols documentation; Receptor Signaling; Research; Resolution; Resources; Rewards; Role; Signal Transduction; Sleep Wake Cycle; Sleeplessness; Specificity; Structure; System; Therapeutic Intervention; Time; Tissues; addiction; biocomputing; brain metabolism; circadian pacemaker; comparative; drug of abuse; fascinate; field study; in vivo; innovation; medical schools; metabolomics; motivated behavior; mouse model; mutant; neurochemistry; novel; prevent; public health relevance; receptor; receptor expression; receptor-mediated signaling; response; reward circuitry; suprachiasmatic nucleus

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.

描述（由申请人提供）：昼夜节律主导着大量的生理、生化和行为反应，它们的破坏可能导致抑郁、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。这一应用程序的智力价值在于在分子水平上破译和解释了一系列引人入胜的观察结果，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起主导作用。这个应用集中在多巴胺能系统的一个主要元素，多巴胺D2受体（D2R）。D2Rs是控制细胞和行为反应的关键角色，这些反应调节运动功能、大脑奖励回路和内分泌控制。有趣的是，这些功能也以昼夜节律的方式调节。我们实验室收集的结果揭示了d2r介导的信号传导与昼夜节律机制控制之间的分子联系。这个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：破译dna