MDMA (?ECSTASY?) ANDTHE DOPAMINE TRANSPORTER

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。3，4-亚甲二氧基甲基苯丙胺（MDMA，摇头丸）对5-羟色胺神经元产生广泛的心理效应和神经毒性，这归因于5-羟色胺神经元通过5-羟色胺转运体（SERT）的选择性转运。MDMA对多巴胺神经元的影响仍然存在争议。DAT与MDMA效应的相关性通过我们证明（3 H）MDMA对人类多巴胺转运蛋白（DAT）和SERT的亲和力相似而得到加强。我们对急性（1 mg/kg，n = 4）或重复使用MDMA（1.5 mg/kg，4个月内18次给药，n=4）的猴子进行了纹状体DAT的PET成像。结果：用（11 C）阿托烷观察DAT的MDMA占用率，尚无定论。在2/4的恒河猴中，急性MDMA取代Caltropane结合占据DAT的30%，但在2/4的猴子中，（11 C）altropane结合增加。与（11 C）CFT重复，MDMA始终增加DAT结合潜力121 +/- 7.5%（n = 4）。食蟹猴重复暴露于MDMA导致末次给药后2周DAT结合潜力降低18%（p <0.03）。讨论内容：可以想象，急性剂量的MDMA后DAT结合潜力增加（6/8个实验）反映了细胞表面DAT或MDMA诱导的DAT成像探针从其他部位释放的可用性增加。重复暴露于MDMA后DAT结合电位的小但一致的损失可能反映了DA神经元的损失、DAT的补偿性下调或MDMA诱导的DAT内化。MDMA对DAT和DA神经元的调节需要进一步研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 3, 4-methylenedioxymethamphetamine (MDMA, ecstasy) produces a broad spectrum of psychological effects and neurotoxicity to serotonin neurons, attributed to selective transport by the serotonin transporter (SERT) by serotonin neurons. MDMA effects on dopamine neurons remain controversial. The relevance of DAT to MDMA effects was reinforced by our demonstration that (3H)MDMA affinity for the human dopamine transporter (DAT) and SERT are similar. We conducted PET imaging of striatum DAT in monkeys treated acutely (1 mg/kg, n = 4) or repeatedly with MDMA (1.5 mg/kg, 18 doses in 4 months, n=4). Results: MDMA occupancy of the DAT, viewed with (11C)altropane, was inconclusive. In 2/4 rhesus monkeys, acute MDMA displaced Caltropane binding to occupy 30% of the DAT, but in 2/4 monkeys, (11C)altropane binding increased. Repeated with (11C)CFT, MDMA consistently increased DAT binding potential by 121 +/- 7.5% (n = 4). Repeated exposure of cynomolgus monkeys to MDMA resulted in an 18% decrease in DAT binding potential (p less than 0.03) two weeks after the last dose. Discussion: Conceivably, the increased DAT binding potential (6/8 experiments) after an acute dose of MDMA reflects increased availability of cell surface DAT or MDMA-induced release of the DAT imaging probe from other sites. The small but consistent loss of DAT binding potential following repeated exposure to MDMA may reflect loss of DA neurons, compensatory down-regulation of the DAT, or MDMA-induced DAT internalization. MDMA modulation of the DAT and DA neurons warrants further investigation.