MDMA (?ECSTASY?) ANDTHE DOPAMINE TRANSPORTER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。3，4-亚甲基二氧基甲基苯丙胺(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，归因于5-羟色胺转运体(SERT)由5-羟色胺神经元选择性转运。MDMA对多巴胺神经元的影响仍然存在争议。DAT与MDMA效应的相关性得到了加强，因为我们证明了(~3H)MDMA对人多巴胺转运体(DAT)和SERT的亲和力是相似的。我们对急性注射MDMA(1 mg/kg，n=4)或重复注射MDMA(1.5 mg/kg，4个月18次)的猕猴进行了纹状体DAT的PET显像。结果：用(11C)阿托品观察DAT的MDMA占有率是不确定的。在2/4猕猴中，急性MDMA取代了钙托烷结合，占DAT的30%，但在2/4恒河猴中，(11C)阿托品结合增加。与(11C)CFT重复，MDMA使DAT结合电位持续增加121+/-7.5%(n=4)。食蟹猴反复暴露于MDMA后，在最后一次给药两周后，DAT结合电位下降了18%(p<0.03)。讨论：可以想象，急性剂量的MDMA后DAT结合潜力的增加(6/8实验)反映了细胞表面DAT的可用性增加或MDMA诱导的DAT成像探针从其他部位释放。重复暴露于MDMA后，DAT结合电位的轻微但持续的丢失可能反映了DA神经元的丢失、DAT的代偿性下调或MDMA诱导的DAT内化。MDMA对DAT和DA神经元的调节作用值得进一步研究。

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.