Imaging dopamine receptor adaptations and signaling pathways with combined PET/fMRI-Supplement

使用 PET/fMRI 补充品对多巴胺受体适应和信号通路进行成像

• 批准号: 10399849
• 负责人: Christin Y. Sander
• 金额: $ 1.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-09 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399849
• 关键词: Brain; Complex; Development; Dopamine Receptor; Drug Addiction; Drug Exposure; Drug Targeting; Drug usage; Evolution; Functional Magnetic Resonance Imaging; Genetic; Glutamate Receptor; Goals; Grant; Image; Intervention; Lead; Maintenance; Measures; Mediating; Mental disorders; Multimodal Imaging; Neurobiology; Outcome; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Positron-Emission Tomography; Prevention; Rewards; Role; Signal Pathway; Signal Transduction; Substance abuse problem; Synapses; System; Testing; addiction; biophysical model; dopamine D3 receptor; dopamine system; drug action; drug of abuse; improved; in vivo; neurobehavioral disorder; nonhuman primate; novel strategies; prevent; psychologic; receptor; receptor internalization; trafficking

Project Summary Drug addiction is a complex neuro-behavioral disorder, involving pharmacological, psychological and genetic influence. The dopamine receptor system plays a highly relevant role for mechanisms underlying reward and addiction. At the synaptic level, sensitization is mediated through dynamic mechanisms, such as receptor internalization; at the whole-brain level, adaptation is reflected through dynamic changes in brain signaling. These dynamic changes, and how drug exposure or treatment can alter them, are still not well understood in vivo but are a critical step towards improving treatment options and outcomes for substance abuse and related psychiatric disorders. The goal of this grant is to apply in vivo with multi-modal imaging in order to investigate how specific pharmacological interventions and stimulant drugs of abuse modulate receptor adaptation mechanisms of the dopamine receptor system, and test novel approaches to prevent such adaptation mechanisms. State-of-the-art integrated positron emission tomography (PET) with functional magnetic resonance imaging (fMRI) will be used to image receptor trafficking dynamics using drugs that are known to induce receptor internalization at D2/D3 dopamine receptors, and then measure these adaptations for stimulants drugs of abuse. Non-human primates will be imaged to establish dynamic relationships between receptor occupancy (PET) and functional activation (fMRI). Together with biophysical modeling, quantification of receptor trafficking rates and their influence on functional signaling will be quantified. Finally, the involvement of the glutamate receptor system will be tested as an approach to modulate or prevent receptor trafficking as induced by drugs of abuse. This approach will help unravel the action of drugs targeted at the dopamine systems and their role in the neurobiological evolution of the development, maintenance and eventual prevention and treatment of drug addiction.

项目摘要 药物成瘾是一种复杂的神经行为疾病，涉及药理，心理和遗传 影响。多巴胺受体系统在奖励的基础机制和 瘾。在突触水平上，敏化是通过动态机制（例如受体）介导的 内在化；在整个脑部水平上，适应通过大脑信号传导的动态变化反映。 这些动态的变化以及药物暴露或治疗如何改变它们，仍然不太了解 体内，但是改善治疗方案和滥用药物及相关结果的关键一步 精神疾病。该赠款的目的是使用多模式成像进行体内应用，以调查 滥用的特定药理干预措施和刺激性药物如何调节受体适应 多巴胺受体系统的机制，并测试了防止这种适应的新方法 机制。 具有功能性磁共振的最先进的正电子发射断层扫描（PET） 成像（fMRI）将用于使用已知诱导的药物来对受体运输动力学进行图像图像 D2/D3多巴胺受体的受体内在化，然后测量这些适应剂的兴奋剂 滥用药物。非人类灵长类动物将成像以在受体之间建立动态关系 占用（PET）和功能激活（fMRI）。与生物物理建模一起定量 受体运输率及其对功能信号传导的影响将被量化。最后，参与 谷氨酸受体系统的测试将作为调节或防止受体运输的方法 由滥用药物引起。这种方法将有助于揭示针对多巴胺的药物的作用 系统及其在开发，维护和最终的神经生物学演变中的作用 预防和治疗药物成瘾。