PET Imaging of Serotonin Transmission in MDMA Users

描述（由申请人提供）：娱乐性药物（+/-）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正在增加。MDMA是一种有效的5-羟色胺（5-HT）释放剂。在动物中，暴露于MDMA与5-HT神经元的长期损伤有关。由于在人体中使用的剂量与已知在动物中产生5-HT神经元损伤的剂量重叠，因此非常严重的担忧是，娱乐性使用MDMA可能导致长期的5-HT神经毒性。5-HT神经毒性可能导致神经认知障碍，行为控制改变，易患情绪和焦虑障碍。

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.