[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: 9763544
• 负责人: ROBERT MICHAEL KESSLER
• 金额: $ 48.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-25 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763544
• 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; Executive Dysfunction; 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; Reproducibility; Rewards; Risk Factors; Role; Schedule; Short-Term Memory; Signal Transduction; 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; methamphetamine effect; methamphetamine use; minimally invasive; neurotransmission; psychiatric symptom; psychostimulant; psychotic symptoms; 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）：mGluR 5受体是一种I型代谢型谷氨酸能受体，其与许多脑疾病密切相关，包括精神兴奋剂药物滥用、脆性X染色体综合征、亨廷顿病、抑郁症和焦虑症，以及在帕金森病的运动障碍中发挥重要作用。尽管其在这些疾病中的重要性，但由于缺乏适当的成像方法，关于mGluR 5功能的人类数据一直缺乏。最近发现了mGluR 5受体的新PET放射性配体;动物和初步人体研究表明，[18 F]FPEB是最有前途的。在[18 F]FPEB可用于临床研究之前，需要进行[18 F]FPEB的辐射剂量测定的人体研究、区域mGluR 5水平定量方法的验证以及这些估计值的重测可靠性。本申请的R21阶段将提供mGluR 5受体未来临床研究PET研究设计所需的数据。 本申请的R33阶段将研究mGluR 5受体在甲基苯丙胺（METH）滥用中的作用。虽然METH成瘾的发展与其显著和快速升高细胞外多巴胺水平的能力有关，但动物研究表明，重复精神兴奋剂给药在腹侧纹状体中产生增加的mGluR 5受体水平和高强直水平的mGluR 5介导的神经传递，这似乎是维持METH成瘾的关键因素。选择性mGluR 5拮抗剂逆转增加的紧张性mGluR 5信号传导和METH在动物中的成瘾作用。其他研究表明，在抑郁症中观察到额叶皮质mGluR 5受体水平降低，并且额叶皮质mGluR 5神经传递介导认知功能，包括METH滥用者受损的执行功能。抑郁症状和执行功能受损是METH滥用者复吸的重要危险因素。本申请的R33阶段的目标是使用PET [18 F]FPEB研究测量METH滥用者的局部mGluR 5水平，并将局部mGluR 5受体水平与METH滥用者中观察到的改变的奖励行为、认知障碍、精神症状以及METH终身使用相关联。拟议的研究将是第一次研究mGluR 5受体在人类滥用甲基苯丙胺，并将显着提高我们的mGluR 5受体在人类滥用甲基苯丙胺的作用的知识。