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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要严重脑损伤后对意识障碍（DOC）患者的研究暗示了功能障碍前脑介质功能障碍是基础机制的钥匙。前脑 DOC中的代谢明显下调，在高度详细的大脑区域中认知行为表明所需的突触背景活动水平的崩溃一致的目标指导行为和唤醒调节。由于多巴胺水平是主要的这些前脑结构内突触背景活动水平的控制器和调节兴奋性谷氨酸能稳态，我们建议研究突触前的特定贡献创伤后文档中谷氨酸能神经传递的多巴胺功能。现在的目的研究是为了测量代谢型谷氨酸受体5在主要谷氨酸酯结构中的占用率大脑在休息时使用[18F] FPEB-PET，并在与Amantadine进行短暂的药理学挑战之后 NMDA-R拮抗剂，L-DOPA和Amantadine + L-DOPA。在文档中使用这种新技术将表征突触前缺乏症与合成和/或释放多巴胺的相关性前脑介质的兴奋性中间神经元的最终调节。尚不清楚谷氨酸能神经传递是否受到与 DOC，如果这种情况是前脑突触前多巴胺能衰竭的继发中环（即下调）。由于我们以前确定了突触前的存在由于多巴胺的生物合成失败，这些受试者的多巴胺能不足，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l-dopa）系统恢复体内平衡。因此，我们建议使用创伤后DOC的患者使用 [18F] FPEB-PET在休息和遵循旨在增加谷氨酸和增加的药理挑战之后多巴胺释放。