[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: 8243362
• 负责人: RONALD L COWAN
• 金额: $ 24.82万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243362
• 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. PUBLIC HEALTH RELEVANCE: While the mGluR5 receptor has been implicated in the pathophysiology of a number of important brain disorders until the recent discovery of radioligands such as [18F]FPEB there have been no radioligands for studying mGluR5 function in humans. The R21 phase of this application will perform human PET [18F]FPEB studies which are needed prior to performance of clinical research human studies of the mGluR5 using [18F]FPEB, radiation dosimetry, quantitative modeling, and test-retest reproducibility and reliability. The R33 phase of this application will study regional brain mGluR5 levels in methamphetamine abusers, and their relationships to the impairments in reward behaviors, cognitive function, and psychiatric symptoms seen in methamphetamine abusers as well as to lifetime methamphetamine use.

描述（由申请人提供）：mGluR5受体是一种I型代谢型谷氨酸能受体，与许多脑部疾病（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）密切相关，并在帕金森病的运动障碍中发挥重要作用。尽管它在这些疾病中很重要，但由于缺乏适当的成像方法，关于mGluR5功能的人类数据缺乏。最近发现了mGluR5受体的新的PET放射性配体；动物和初步的人体研究表明[18F]FPEB是最有希望的。在[18F]FPEB可用于临床研究之前，需要进行[18F]FPEB的人体辐射剂量学研究、区域mGluR5水平定量方法的验证以及这些估计的重测可靠性。该申请的R21期将提供mGluR5受体未来临床研究PET研究设计所需的这些数据。该申请的R33阶段将检查mGluR5受体在甲基苯丙胺（冰毒）滥用中的作用。虽然甲基苯丙胺成瘾的发展与其显著和快速提高细胞外多巴胺水平的能力有关，但动物研究表明，反复使用精神兴奋剂会增加mGluR5受体水平，并使mGluR5介导的腹侧纹状体神经递质呈高张力水平，这似乎是维持甲基苯丙胺成瘾的关键因素。选择性mGluR5拮抗剂逆转了动物中增加的强直性mGluR5信号传导和甲基苯丙胺的成瘾效应。其他研究表明，抑郁症患者额叶皮质mGluR5受体水平下降，额叶皮质mGluR5神经传递介导甲基苯丙胺滥用者受损的认知功能，包括执行功能。甲基安非他明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研究测量冰毒滥用者的区域mGluR5水平，并将区域mGluR5受体水平与冰毒滥用者的奖赏行为改变、认知障碍、精神症状以及终生冰毒使用联系起来。本研究将是首次研究mGluR5受体在人类冰毒滥用中的作用，并将大大提高我们对mGluR5受体在人类冰毒滥用中的作用的认识。