[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I型的A型代谢剂谷氨酸能受体，与多种脑部疾病有关，包括精神刺激性药物滥用，脆弱的X综合征，亨廷顿氏病，抑郁症和焦虑症以及在帕克森病中发挥重要作用。尽管在这些疾病中具有重要意义，但由于缺乏适当的成像方法，人类对MGLUR5功能的数据很少。最近发现了用于MGLUR5受体的新PET放射线。动物和最初的人类研究表明，[18F] FPEB是最有前途的。在[18F] FPEB可以用于临床研究之前，对[18F] FPEB的辐射剂量测定的人类研究，区域MGLUR5水平定量方法的验证以及需要执行这些估计值的重测可靠性。该应用程序的R21阶段将提供这些数据，这些数据是设计MGLUR5受体的未来临床研究PET研究所需的数据。 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。虽然甲基成瘾的发展与其显着和迅速升高细胞外多巴胺水平的能力有关，但动物研究表明，重复的心理刺激性给药会产生升高的MGLUR5受体水平，而MGLUR5的MGLUR5辅助介导的神经递质的高水平在腹侧纹状体中似乎是对维持甲基甲基添加的关键因素的关键因素。选择性MGLUR5拮抗剂逆转了增加的补品MGLUR5信号传导和甲基甲基苯酚对动物的成瘾作用的逆转。其他研究表明，在抑郁症中可以看到额叶皮质MGLUR5受体水平降低，而额叶皮质MGLUR5神经传递介导了包括在甲基苯丙胺施肥者中受损的执行功能，其中包括执行功能。抑郁症症状的抑郁症状和执行功能受损是药物复发的重要危险因素。该应用的R33阶段的目标是使用PET [18F] FPEB研究来测量甲基滥用者的区域MGLUR5水平，并将区域MGLUR5受体水平与改变的奖励行为，认知障碍，精神病症状相关联，在甲基甲基苯丙胺和生命周期中使用的精神症状。拟议的研究将是人类中MGLUR5受体滥用中MGLUR5受体的第一批研究，并将显着增强我们对MGLUR5受体在人类滥用甲基甲基苯酚中的作用的了解。 公共卫生相关性：虽然MGLUR5受体与许多重要的脑疾病的病理生理有关，直到最近发现[18F] FPEB等放射性物体（例如[18F] FPEB），但在人类中没有用于研究MGLUR5功能的放射性物体。该应用的R21阶段将进行人类PET [18F] FPEB研究，在进行MGLUR5进行临床研究之前需要使用[18F] FPEB，辐射剂量学，定量建模和测试 - 重新测试可重复性和可靠性。该应用的R33阶段将研究甲基苯丙胺滥用器中的区域脑MGLUR5水平，以及它们与奖励行为，认知功能和精神症状的损害的关系，以及甲基苯丙胺施用者以及终生甲基苯丙胺的使用。