Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates.
Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates.
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DOI：
10.1038/npp.2013.331
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发表时间：
2014-05
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影响因子：
--
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5-羟色胺(5-羟色胺)转运体(SERT)底物如芬氟拉明和3，4-亚甲基二氧甲基苯丙胺会导致脑部5-羟色胺的长期耗竭，而其他某些底物则不会。SERT底物产生的5-羟色胺缺失依赖于转运蛋白，但具体机制尚不清楚。在这里，我们比较了几种SERT底物：芬氟拉明、d-芬氟拉明、1-(间氯苯基)哌嗪(MCPP)和1-(间三氟甲基苯基)胡椒碱(TFMPP)的药理作用，以建立急性药物机制与长期5-羟色胺耗竭倾向之间的关系。在体内对大鼠伏隔核进行微透析，以检测同一受试者的急性5-羟色胺释放和长期耗竭。体外测定大鼠脑突触体内[~3H]-5-羟色胺的外流和表达SERT的非洲爪哇卵母细胞转运蛋白介导的离子电流。当给大鼠重复给药(6 mg/kg，ip，4次剂量)时，所有药物都会产生细胞外5-羟色胺的持续大幅升高(>；5倍)，对多巴胺的影响很小。重要的是，给药2周后，只有芬氟拉明和d-芬氟拉明暴露的大鼠表现出脑组织5-羟色胺的耗竭。所有受试药物均可引起突触体对氟西汀敏感的[~3H]5-羟色胺外流，但d-芬氟拉明及其活性代谢物d-去甲苯氟拉明引起的SERT介导的电流明显大于苯基哌嗪。我们的数据证实，药物诱导的5-羟色胺释放可能并不介导5-羟色胺的耗竭。然而，转运蛋白介导的内向电流的大小可能是导致5-羟色胺缺陷的一系列事件的关键因素。这一假说值得进一步研究，特别是考虑到针对SERT的设计药物越来越受欢迎。
Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [3H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [3H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.
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影响因子：
4.7
作者：
Hilber, B;Scholze, P;Sitte, HH
通讯作者：
Sitte, HH
影响因子：
3.6
作者：
JOHNSON, MP;NICHOLS, DE
通讯作者：
NICHOLS, DE
非竞争性ibogaine抑制5-羟色胺和多巴胺转运蛋白的机械基础。
DOI：
10.1074/jbc.m112.343681
发表时间：
2012-05-25
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bulling S;Schicker K;Zhang YW;Steinkellner T;Stockner T;Gruber CW;Boehm S;Freissmuth M;Rudnick G;Sitte HH;Sandtner W
通讯作者：
Sandtner W
影响因子：
158.5
作者：
Connolly, HM;Crary, JL;Schaff, HV
通讯作者：
Schaff, HV
影响因子：
7.6
作者：
Eriksson, E;Engberg, G;Nissbrandt, H
通讯作者：
Nissbrandt, H