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

结合 PET/fMRI 对多巴胺受体适应和信号通路进行成像

• 批准号: 10226211
• 负责人: Christin Y. Sander
• 金额: $ 24.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226211
• 关键词: Address; Agonist; Binding; Brain; Central Nervous System Stimulants; Clinical; Complex; Coupled; Coupling; Development; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Dopaminergic Agents; Dose; Drug Addiction; Drug Exposure; Drug Targeting; Drug usage; Event; Evolution; Functional Magnetic Resonance Imaging; GTP-Binding Proteins; Genetic; Glutamate Receptor; Glutamates; Goals; Grant; Hour; Image; Injections; Intervention; Lead; Link; Maintenance; Measures; Mediating; Mental disorders; Mentors; Modeling; Molecular Conformation; Multimodal Imaging; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neurobiology; Neuropharmacology; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Play; Positron-Emission Tomography; Prevention; Raclopride; Receptor Signaling; Recovery; Research; Rewards; Role; Sensory Receptors; Signal Pathway; Signal Transduction; Substance abuse problem; Synapses; System; Testing; Time; Training; Work; addiction; beta-arrestin; biophysical model; brain pathway; career; desensitization; dopamine D3 receptor; dopamine system; drug action; drug of abuse; experimental study; imaging modality; improved; in vivo; innovation; neuroadaptation; neurobehavioral disorder; neurochemistry; non-invasive system; nonhuman primate; novel strategies; prevent; psychologic; receptor; receptor binding; receptor internalization; response; trafficking; translation to humans

Project Summary/Abstract 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 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.

项目总结/摘要 药物成瘾是一种复杂的神经行为障碍，涉及药理学、心理学和遗传学等多个方面 影响力的社会多巴胺受体系统在奖赏机制中起着高度相关的作用， 成瘾在突触水平，敏化是通过动态机制介导的，例如受体介导的。 内在化;在全脑水平，适应是通过大脑信号的动态变化来反映的。 这些动态变化，以及药物暴露或治疗如何改变它们，仍然没有得到很好的理解， 但这是朝着改善药物滥用和相关疾病的治疗选择和结果迈出的关键一步。 精神疾病该基金的目标是应用体内多模态成像，以研究 特定药物干预和滥用兴奋剂如何调节受体适应 多巴胺受体系统的机制，并测试新的方法来防止这种适应 机制等 最先进的集成正电子发射断层扫描（PET）与功能性磁共振 功能磁共振成像（fMRI）将用于成像受体运输动力学使用药物，已知诱导 受体内化在D2/D3多巴胺受体，然后测量这些适应兴奋剂 滥用药物。将对非人灵长类动物进行成像，以建立受体之间的动态关系。 占据（PET）和功能激活（fMRI）。与生物物理建模一起， 受体运输速率及其对功能信号传导的影响将被量化。最后，参与 将测试谷氨酸受体系统作为防止受体运输的方法， 滥用药物。这种方法将有助于揭示靶向多巴胺系统的药物的作用， 在发展、维持和最终预防的神经生物学进化中的作用， 戒毒治疗。