Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain.
Eur J Pharmacol. 2012 Jan 15;674(2-3):337-44. doi: 10.1016/j.ejphar.2011.10.033. Epub 2011 Nov 3.
(±)-3,4-Methylenedioxymethamphetamine (MDMA) is an illicit drug that evokes transporter-mediated release of serotonin (5-HT) in the brain. 5-HT transporter (SERT) proteins are also expressed in non-neural tissues (e.g., blood), and evidence suggests that MDMA targets platelet SERT to increase plasma 5-HT. Here we tested two hypotheses related to the effects of MDMA on circulating 5-HT. First, to determine if MDMA metabolites might contribute to actions of the drug in vivo, we used in vitro microdialysis in rat blood specimens to examine the effects of MDMA and its metabolites on plasma 5-HT. Second, to determine whether effects of MDMA on plasma 5-HT might be used as an index of central SERT activity, we carried out in vivo microdialysis in blood and brain after intravenous MDMA administration. The in vitro results show that test drugs evoke dose-related increases in plasma 5-HT ranging from two- to sevenfold above baseline, with MDMA and its metabolite, (±)-3,4-methylenedioxyamphetamine (MDA), producing the largest effects. The ability of MDMA and related analogs to elevate plasma 5-HT is correlated with their potency as SERT substrates in rat brain synaptosomes. The in vivo results reveal that MDMA causes concurrent increases in extracellular 5-HT in blood and brain, but there are substantial individual differences in responsiveness to the drug. Collectively, our findings indicate that MDMA and its metabolites increase plasma 5-HT by a SERT-dependent mechanism, and suggest the possibility that measures of evoked 5-HT release in blood may reflect central SERT activity.
（±）-3,4-亚甲二氧基甲基苯丙胺（MDMA）是一种非法药物，它会引起大脑中 5-羟色胺（5-HT）的转运体介导释放。5-羟色胺转运体（SERT）蛋白也在非神经组织（如血液）中表达，有证据表明 MDMA 靶向血小板 SERT 以增加血浆 5-HT。在这里，我们检验了与 MDMA 对循环 5-HT 的作用相关的两个假设。首先，为了确定 MDMA 代谢物是否会影响药物在体内的作用，我们使用大鼠血液标本中的体外微透析来研究 MDMA 及其代谢物对血浆 5-HT 的影响。其次，为了确定 MDMA 对血浆 5-HT 的作用是否可以作为中枢 SERT 活性的指标，我们在静脉注射 MDMA 后进行了血液和大脑的体内微透析。体外结果表明，测试药物会引起血浆 5-HT 的剂量依赖性增加，其幅度从基线的两倍到七倍不等，其中 MDMA 和其代谢物（±）-3,4-亚甲二氧基苯丙胺（MDA）产生的效果最大。MDMA 和相关类似物升高血浆 5-HT 的能力与其作为大鼠脑突触体中 SERT 底物的效力相关。体内结果表明，MDMA 导致血液中外源性 5-HT 的同时增加，但对药物的反应存在很大的个体差异。总的来说，我们的发现表明，MDMA 及其代谢物通过 SERT 依赖的机制增加血浆 5-HT，并提示血液中诱导的 5-HT 释放的测量可能反映中枢 SERT 活性。
