Evaluation of pharmacologically-induced changes in excitatory glutamatergic neurotransmission of severe TBI patients

药理学诱导的严重 TBI 患者兴奋性谷氨酸能神经传递变化的评估

• 批准号: 9979372
• 负责人: Esteban Andres Fridman
• 金额: $ 25.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979372
• 关键词: Address; Affect; Amantadine; Amphetamines; Anabolism; Anterior; Arousal; Behavior; Binding; Biological; Biological Markers; Brain; Brain Injuries; Brain region; Chronic; Clinical Trials; Cognitive; Conscious; Consciousness Disorders; Deafferentation procedure; Development; Diagnosis; Diagnostic Procedure; Dopamine; Dopamine Receptor; Down-Regulation; Effectiveness; Enzymes; Evaluation; Exhibits; Failure; Functional disorder; Future; Glutamates; Goals; Homeostasis; Impairment; Interneurons; Knowledge; Levodopa; Measurement; Measures; Metabolism; Molecular; N-Methyl-D-Aspartate Receptors; National Institute of Neurological Disorders and Stroke; Neurons; Outcome; Patients; Pharmacodynamics; Pharmacology; Phase; Play; Polypharmacy; Population; Positron-Emission Tomography; Premedication; Process; Prosencephalon; Recovery; Regulation; Research; Rest; Role; Secondary to; Source; Structure; Substantia nigra structure; Synapses; System; TBI Patients; Techniques; Testing; Thalamic structure; Therapeutic Intervention; Traumatic Brain Injury; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; cost; disability; frontal lobe; improved; in vivo; metabotropic glutamate receptor 5; nerve supply; neuroimaging; neuron loss; neuroregulation; neurotransmission; neurotransmitter release; new therapeutic target; nonhuman primate; novel; patient response; postsynaptic; presynaptic; response; reuptake; social; treatment strategy; volunteer

Project Summary Studies in patients with disorders of consciousness (DOC) after severe brain injury implicate dysfunction of the anterior forebrain mesocircuit dysfunction a key underlying mechanism. The anterior forebrain metabolism in DOC is markedly downregulated across brain regions underpinning highly elaborated cognitive behaviors demonstrating a collapse of the level of synaptic background activity required for consistent goal-directed behavior and arousal regulation. Since dopamine levels are one of the primary controllers of the level of synaptic background activity within these forebrain structures and in regulating excitatory glutamatergic homeostasis, we propose to investigate the specific contribution of presynaptic dopamine function in glutamatergic neurotransmission in posttraumatic DOC. The aim of the present study is to measure metabotropic glutamate receptors 5 occupancy in the main glutamatergic structures of the brain using [18F]FPEB-PET at rest and following a short pharmacological challenge with amantadine, an NMDA-R antagonist, following L-DOPA, and amantadine + L-DOPA. Using this novel technique in DOC we will characterize the relevance of a presynaptic deficiency to synthesize and/or release dopamine in the final regulation of excitatory interneurons of the anterior forebrain mesocircuit. It is unknown whether glutamatergic neurotransmission is affected across the population of subjects with DOC and, if this condition is secondary to a presynaptic dopaminergic failure of the anterior forebrain mesocircuit (i.e., down-regulation). Since we previously identified the existence of a presynaptic dopaminergic deficit in these subjects due to a failure in the biosynthesis of dopamine, we will evaluate if by providing the main biological substrate of the biosynthesis process (i.e., L-DOPA) the glutamatergic system regains homeostasis. We therefore propose to investigate patients with posttraumatic DOC using [18F]FPEB-PET at rest and following short pharmacological challenges aimed at increasing glutamate and dopamine release.

项目概要 对严重脑损伤后意识障碍 (DOC) 患者的研究表明，大脑功能障碍 前脑介导电路功能障碍是一个关键的潜在机制。前部前脑 DOC 中的代谢在支撑高度精细的大脑区域中显着下调 认知行为表明突触背景活动水平崩溃 一致的目标导向行为和唤醒调节。由于多巴胺水平是主要因素之一 这些前脑结构内突触背景活动水平的控制器以及调节 兴奋性谷氨酸稳态，我们建议研究突触前的具体贡献 多巴胺在创伤后 DOC 谷氨酸能神经传递中的功能。目前的目的 研究的目的是测量代谢型谷氨酸受体 5 在主要谷氨酸能结构中的占据情况 在休息时使用 [18F]FPEB-PET 并在使用金刚烷胺（一种 NMDA-R拮抗剂，继L-DOPA和金刚烷胺+L-DOPA之后。在 DOC 中使用这项新技术，我们 将表征突触前缺陷与合成和/或释放多巴胺的相关性 前脑中间回路兴奋性中间神经元的最终调节。 目前尚不清楚谷氨酸能神经传递是否在患有该疾病的受试者群体中受到影响。 DOC，如果这种情况继发于前脑突触前多巴胺能衰竭 介观电路（即下调）。由于我们之前确定了突触前的存在 由于多巴胺生物合成失败，这些受试者的多巴胺能缺陷，我们将评估 如果通过提供生物合成过程的主要生物底物（即左旋多巴），谷氨酸能 系统恢复稳态。因此，我们建议使用以下方法来调查患有创伤后 DOC 的患者： [18F]FPEB-PET 处于休息状态和短期药理挑战后，旨在增加谷氨酸和 多巴胺释放。