PET Imaging of Serotonin Transmission in MDMA Users

描述(由申请人提供)：娱乐用毒品(+/-)3，4-亚甲基二氧基甲基苯丙胺(MDMA；“摇头丸”)的使用在美国和世界上都在增加。MDMA是一种有效的5-羟色胺(5-HT)释放剂。在动物中，接触MDMA与5-羟色胺神经元的长期损伤有关。由于人类使用的剂量与动物5-羟色胺神经元损伤的已知剂量重叠，人们非常严重地担心，娱乐使用MDMA可能会导致长期的5-羟色胺神经毒性。5-羟色胺的神经毒性可能导致神经认知障碍、行为控制改变以及易患情绪和焦虑症。 核医学的最新进展使活体人脑中5-羟色胺相关蛋白的直接定量成为可能。5-羟色胺转运体(SERT)仅位于5-羟色胺轴突终末。最近用PET和SPECT对SERT进行的成像研究报告了一些数据，表明大量使用MDMA的人SERT密度降低，这一发现在女性使用者中可能比在男性使用者中更明显。此外，对突触后5-HT2A受体的初步成像研究报告称，MDMA使用者中该受体的密度增加，这一发现可能反映了5-羟色胺耗竭导致的表达上调。然而，这些研究是使用第一代PET和SPECT放射性示踪剂进行的，这些示踪剂具有低选择性或低信噪比。由于这些技术限制，5-羟色胺系统是否以及在多大程度上适用于娱乐MDMA用户仍不确定。 鉴于这一问题对公共卫生的重要性与日俱增，我们建议利用放射性配体发展的最新进展来研究这一问题。[11C]DASB和[11C]MDL100907分别是用于SERT和5-HT2A受体成像的新型高选择性放射性示踪剂。与第一代5-羟色胺放射性配基相比，这些放射性示踪剂提供了极大的图像质量改进，并能够可靠地定量它们在活脑中的目标蛋白。 30名重度吸毒者(15名男性和15名女性)和30名匹配的对照组将在18天的监测戒断后接受正电子发射计算机断层扫描[11C]DASB和[11C]MDL 100907。有待检验的假设是，与对照组相比，服用MDMA的人SERT和5-HT2A受体密度分别降低和增加，这些变化在女性比男性更明显，并与以前接触MDMA的程度有关。

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.