[18F]FPEB Studies of the mGluR5 Receptor and Methamphetamine Abuse

[18F]mGluR5 受体和甲基苯丙胺滥用的 FPEB 研究

• 批准号: 8460823
• 负责人: RONALD L COWAN
• 金额: $ 4.06万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2013-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460823
• 关键词: Age; Animals; Anxiety Disorders; Behavior; Bolus Infusion; Brain; Brain Diseases; Cerebrum; Chronic; Clinical Research; Corpus striatum structure; Data; Development; Disease; Dopamine; Drug abuse; Drug usage; Dyskinetic syndrome; Fragile X Syndrome; Functional disorder; Future; Glutamates; Goals; Human; Huntington Disease; Impaired cognition; Impairment; Impulsivity; Incidence; Knowledge; Maintenance; Measures; Mediating; Memory; Mental Depression; Methamphetamine; Methamphetamine dependence; Methods; Modeling; Motor; Parkinson Disease; Performance; Phase; Plasma; Play; Positron-Emission Tomography; Prefrontal Cortex; Radiometry; Receptor Signaling; Relapse; Reproducibility; Rewards; Risk Factors; Role; Schedule; Short-Term Memory; Signal Transduction; Symptoms; Testing; Tissues; Up-Regulation; Validation; Ventral Striatum; cognitive change; cognitive function; depressive symptoms; design; drug relapse; executive function; extracellular; frontal lobe; human subject; imaging modality; methamphetamine abuse; neurotransmission; psychostimulant; putamen; radioligand; receptor; receptor function; research study; sex; uptake

DESCRIPTION (provided by applicant): The mGluR5 receptor is a Type I metabotropic glutamatergic receptor which is critically involved in a number of brain disorders including psychostimulant drug abuse, the Fragile X syndrome, Huntington's disease, depression, and anxiety disorders as well as playing an important role in motor dyskinesias in Parkinsons disease. Despite its importance in these disorders there has been a paucity of data in humans regarding mGluR5 function due to a lack of appropriate imaging methods. Recently new PET radioligands for the mGluR5 receptors have been discovered; animal and initial human studies suggest that [18F]FPEB is the most promising. Before [18F]FPEB can be used in clinical research, studies in humans of radiation dosimetry of [18F]FPEB , validation of methods of quantitation of regional mGluR5 levels, and the test-retest reliability of these estimates need to be performed. The R21 phase of this application will provide these data which are needed for design of future clinical research PET studies of the mGluR5 receptor. The R33 phase of this application will examine the role of the mGluR5 receptor in methamphetamine (METH) abuse. While the development of METH addiction has been related to its ability to markedly and rapidly elevate extracellular dopamine levels, animal studies indicate that repeated psychostimulant administration produces increased mGluR5 receptor levels and a high tonic level of mGluR5 mediated neurotransmission in the ventral striatum which appears to be a critical factor in the maintenance of METH addiction. Selective mGluR5 antagonists reverse both the increased tonic mGluR5 signaling and the addictive effects of METH in animals. Other studies indicate that decreased frontal cortical mGluR5 receptor levels are seen in depression and that frontal cortical mGluR5 neurotransmission mediates cognitive functions including executive function which are impaired in METH abusers. Depressive symptoms and impaired executive function in METH abusers are significant risk factors for drug relapse. The goals of the R33 phase of this application are to measure regional mGluR5 levels in METH abusers using PET [18F]FPEB studies, and to correlate regional mGluR5 receptor levels with the altered reward behaviors, cognitive impairments, psychiatric symptoms seen in METH abusers and with lifetime METH use. The proposed studies will be the first studies the of mGluR5 receptor in METH abuse in humans, and will significantly enhance our knowledge of the role of the mGluR5 receptor in humans abusing METH.

描述（由申请人提供）：mGluR5受体是I型代谢型谷氨酸受体，其与许多脑部疾病密切相关，包括精神兴奋剂药物滥用、脆性X综合征、亨廷顿病、抑郁症和焦虑症，并且在帕金森病的运动运动障碍中发挥重要作用。尽管 mGluR5 在这些疾病中很重要，但由于缺乏适当的成像方法，有关人类 mGluR5 功能的数据仍然很少。最近发现了针对 mGluR5 受体的新 PET 放射性配体；动物和初步人体研究表明 [18F]FPEB 是最有前途的。在 [18F]FPEB 可用于临床研究之前，需要对人体进行 [18F]FPEB 辐射剂量研究、区域 mGluR5 水平定量方法的验证以及这些估计值的重测可靠性研究。该应用的 R21 阶段将提供 mGluR5 受体未来临床研究 PET 研究设计所需的数据。 该应用的 R33 阶段将检查 mGluR5 受体在甲基苯丙胺 (METH) 滥用中的作用。虽然冰毒成瘾的发生与其显着、快速升高细胞外多巴胺水平的能力有关，但动物研究表明，重复服用精神兴奋剂会增加 mGluR5 受体水平，并导致腹侧纹状体中 mGluR5 介导的神经传递水平升高，这似乎是维持冰毒成瘾的关键因素。选择性 mGluR5 拮抗剂可逆转动物体内增强的 mGluR5 信号传导和 METH 的成瘾作用。其他研究表明，抑郁症患者的额叶皮质 mGluR5 受体水平降低，额叶皮质 mGluR5 神经传递介导认知功能，包括冰毒滥用者受损的执行功能。甲基苯丙胺滥用者的抑郁症状和执行功能受损是药物复发的重要危险因素。本应用 R33 阶段的目标是使用 PET [18F]FPEB 研究测量 METH 滥用者的区域 mGluR5 水平，并将区域 mGluR5 受体水平与 METH 滥用者中观察到的奖赏行为改变、认知障碍、精神症状以及终生 METH 使用相关联。拟议的研究将是 mGluR5 受体在人类冰毒滥用中的首次研究，并将显着增强我们对 mGluR5 受体在人类冰毒滥用中作用的认识。