Role of dopamine-glutamate receptor heteromers and downstream nuclear calcium signaling in addiction

多巴胺谷氨酸受体异聚体和下游核钙信号在成瘾中的作用

• 批准号: 284122125
• 负责人: Professor Dr. Hilmar Bading
• 金额: --
• 依托单位: Laboratoire Neuroscience Paris Seine-IBPS (CNRS UMR8246/Inserm U1130)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/284122125?language=en
• 关键词: Role; dopamine; glutamate; receptor; heteromers

Addiction, like other psychiatric disorders, is associated with an imbalance of dopamine (DA) and glutamate (Glu) mediated synaptic transmission in the brain. A central goal of this proposal is to establish means of targeting the crosstalk between DA receptors (DARs) and NMDA-type glutamate receptors (NMDARs), rather than the functions of the individual receptors, which may provide the basis for novel, more specific and effective therapies. Heteromers that are formed by the interaction of DA D1 receptors (D1Rs) and NMDARs in the striatum control synaptic plasticity and cocaine-induced signaling. We will explore the role of DAR/NMDAR heteromers and their downstream nuclear calcium signaling in the development of addiction and identify key targets for the design of novel pharmacological tools to combat addiction. Partners 1 and 2 set up novel approaches to detect DAR/NMDAR heteromers and to block the signaling events associated with them. The modulation of D1R/GluN1 and D2R/GluN2B heteromers will be studied in the entire reward circuitry during cocaine-induced psychomotor sensitization and in the context of natural reward. Our preliminary data indicate a dramatic increase of D1R/GluN1 heteromers in the striatum of mice during psychomotor sensitization. Viral-based approaches will be developed to block, in a region-specific and temporally controlled manner, heteromer formation in order to determine their functions in cocaine addiction. Disruption of D1R/GluN1 heteromers inhibits the generation of nuclear calcium signals in cultured striatal medium-size spiny neurons (MSNs). Partner 3 has established that nuclear calcium transients are critical events linking changes in neuronal activity to gene transcription and memory consolidation. Partners 1 and 3 will study the role of this particular pool of calcium in the context of addiction. Partner 3 will study the dynamics of nuclear calcium signals in the striatum in D1R-MSN or D2R-MSN in freely moving mice during cocaine-induced psychomotor sensitization with or without pretreatment with blockers of heteromer formation. Blockers of nuclear calcium signaling will be used to establish causal links to long-term behavioral adaptations, changes of the neuronal morphology and gene expression profiles. To address the difficulties associated with the use of peptides in pre-clinical/clinical studies, partner 4 will screen a library for non-peptide compounds that target specifically DAR/NMDAR heteromers. Lead compounds will be tested in vitro and in vivo for their ability to disrupt endogenous heteromers, their downstream nuclear calcium signaling and cocaine addiction associated behavioral alterations. This project may lead to a major step forward towards identifying new targets with therapeutic potentials not only for addiction but also for various other psychiatric diseases that are accompanied by dysfunctions of the reward system due to an imbalance of DA and Glu mediated synaptic transmission in the striatum.

与其他精神疾病一样，成瘾与大脑中多巴胺（DA）和谷氨酸（Glu）介导的突触传递失衡有关。本研究的核心目标是建立针对DA受体（dar）和nmda型谷氨酸受体（NMDARs）之间串扰的方法，而不是单个受体的功能，这可能为新的、更特异性和更有效的治疗提供基础。纹状体中由DA D1受体（D1Rs）和NMDARs相互作用形成的异构体控制突触可塑性和可卡因诱导的信号传导。我们将探索DAR/NMDAR异聚体及其下游核钙信号在成瘾发展中的作用，并确定设计新型药物工具以对抗成瘾的关键靶点。合作伙伴1和2建立了检测DAR/NMDAR异构体并阻断与其相关的信号事件的新方法。D1R/GluN1和D2R/GluN2B异构体的调节将在可卡因诱导的精神运动致敏和自然奖励的背景下在整个奖励回路中进行研究。我们的初步数据表明，在精神运动致敏过程中，小鼠纹状体中的D1R/GluN1异构体急剧增加。将发展基于病毒的方法，以特定区域和暂时控制的方式阻止异构体的形成，以确定它们在可卡因成瘾中的作用。破坏D1R/GluN1异构体可抑制培养纹状体中等大小棘神经元（MSNs）核钙信号的产生。合作伙伴3已经确定核钙瞬态是连接神经元活动变化与基因转录和记忆巩固的关键事件。伙伴1和伙伴3将研究这种特殊的钙池在成瘾背景下的作用。搭档3将研究在可卡因诱导的精神运动致敏过程中，自由运动小鼠D1R-MSN或D2R-MSN中纹状体核钙信号的动态变化。核钙信号阻滞剂将用于建立与长期行为适应、神经元形态变化和基因表达谱的因果关系。为了解决在临床前/临床研究中使用肽的困难，合作伙伴4将筛选特异性靶向DAR/NMDAR异聚体的非肽化合物库。铅化合物将在体外和体内测试其破坏内源性异构体、其下游核钙信号和可卡因成瘾相关行为改变的能力。这个项目可能会导致一个重要的步骤，以确定新的目标治疗潜力，不仅对成瘾，而且对各种其他精神疾病，伴随着奖励系统的功能失调，由于DA和谷氨酸介导的突触传递在纹状体中的不平衡。