PET Imaging of Serotonin Transmission in MDMA Users

MDMA 使用者血清素传输的 PET 成像

基本信息

批准号：
6793214
负责人：
MARC A LARUELLE
金额：
$ 41.52万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-15 至 2007-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6793214
关键词：
3,4 methylenedioxymethamphetamine bioimaging /biomedical imaging brain imaging /visualization /scanning clinical research drug abuse gender difference human subject neurotransmitter transport positron emission tomography protein localization radiotracer receptor expression serotonin serotonin receptor serotonin transporter

项目摘要

DESCRIPTION (provided by applicant): The use of the recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') is increasing in the US and the world. MDMA is a potent serotonin (5-HT) releaser. In animals, exposure to MDMA is associated with long-lasting damage to 5-HT neurons. As doses used in humans overlap with doses known to produce lesions of 5-HT neurons in animals, there is a very serious concern that long-term 5-HT neurotoxicity might result from the recreational use of MDMA. 5-HT neurotoxicity might lead to neurocognitive impairment, altered behavioral control, and vulnerability to mood and anxiety disorders. Recent progress in nuclear medicine has enabled direct quantification of 5-HT related proteins in the living human brain. The 5-HT transporter (SERT) is located exclusively on 5-HT axonal terminals. Recent imaging studies of the SERT with PET and SPECT have reported data suggesting that SERT density is decreased in heavy MDMA users, a finding that may be more pronounced in female users than in males. In addition, preliminary imaging studies of the post-synaptic 5-HT2A receptor have reported an increased density of this receptor in MDMA users, a finding that might reflect an upregulation secondary to 5-HT depletion. However, these investigations were carried out with first generation PET and SPECT radiotracers which have low selectivity or low signal to noise ratios. Because of these technical limitations it is still uncertain whether, and to what extend, the 5-HT system is lesioned in recreational MDMA users. Given the growing importance of this question for public health, we propose to capitalize on recent progress in radioligand development to examine this question. [11C]DASB and [11C]MDL100907 are new and highly selective radiotracers for imaging the SERT and 5-HT2A receptor, respectively. These radiotracers provide great improvement in image quality over the first generation of 5-HT radioligands, and enable reliable quantification of their target proteins in the living brain. Thirty (30) heavy MDMA users (15 males and 15 females) and 30 matched MDMA-na?ve controls will undergo PET scans with [11C]DASB and [11C]MDL 100907 following an 18 day period of monitored abstinence. The hypotheses to be tested are that SERT and 5-HT2A receptor densities are decreased and increased, respectively, in MDMA users compared to controls, and that these alterations are more pronounced in females compared to males and related to magnitude of previous MDMA exposure.

描述（由申请人提供）：在美国和世界上，使用休闲药（+/-）3,4-甲基二甲基甲基苯丙胺（MDMA;'ofstasy'）正在增加。 MDMA是有效的5-羟色胺（5-HT）释放器。在动物中，暴露于MDMA与对5-HT神经元的持久损害有关。正如人类中使用的剂量与已知可在动物中产生5-HT神经元病变的剂量重叠，人们非常担心长期5-HT神经毒性可能是由于MDMA的娱乐性使用而导致的。 5-HT神经毒性可能导致神经认知障碍，行为控制的改变以及情绪和焦虑症的脆弱性。核医学的最新进展已使在活的人脑中直接量化5-HT相关的蛋白质。 5-HT转运蛋白（SERT）仅位于5-HT轴突端子上。对使用PET和SPECT的SERT的最新成像研究报告了数据表明，大型MDMA使用者的SERT密度降低，这一发现在女性使用者中可能比男性更为明显。此外，对后突触后5-HT2A受体的初步成像研究报告说，MDMA使用者中该受体的密度增加，这一发现可能反映了继发于5-HT耗竭的上调。但是，这些研究是使用第一代PET和SPECT放射性示例进行的，这些PET和SPECT放射性示例的选择性较低或噪声比。由于这些技术局限性，仍然不确定5-HT系统在娱乐性MDMA用户中是否会生存。鉴于这个问题对公共卫生的重要性越来越重要，我们建议利用放射线发展的最新进展来研究这个问题。 [11C] DASB和[11C] MDL100907分别是用于成像SERT和5-HT2A受体的新型和高度选择性的放射性示例。与第一代5-HT放射性配体相比，这些放射性示例可在图像质量方面有很大的改善，并可以在活大脑中对其靶蛋白进行可靠的定量。在经过18天的监测节制期间，有30（30）个重型MDMA使用者（15名男性和15名女性）和30个匹配的MDMA-NA？VE对照组将接受[11C] DASB和[11C] MDL 100907的PET扫描。要测试的假设是，与对照组相比，在MDMA使用者中，SERT和5-HT2A受体密度分别降低和增加，并且与男性相比，这些改变更为明显，并且与先前的MDMA暴露的大小有关。