Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs.
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs.
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DOI：
10.1186/1471-2210-6-6
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发表时间：
2006-03-03
期刊：
影响因子：
--
通讯作者：
Gu HH
中科院分区：
文献类型：
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作者：
Han DD;Gu HH
质膜神经递质转运蛋白通过重摄取释放的神经递质来终止神经传递。单胺多巴胺、去甲肾上腺素和5-羟色胺（DAT、NET和SERT）的转运蛋白是几种流行的精神兴奋剂滥用药物的靶点。精神兴奋剂对单胺转运蛋白的效力已经由几个实验室研究过。然而，报告的数据存在显著差异，差异高达60倍。此外，在相同的实验中或与人转运蛋白一起沿着比较了来自小鼠的3种单胺转运蛋白的药物效力。需要进一步的研究和系统的比较。在这项研究中，我们比较了五种精神兴奋剂药物在相同细胞背景下抑制人类和小鼠DAT，SERT和NET的效力。可卡因抑制3种转运蛋白的KI值在0.2 - 0.7 μM的窄范围内。相比之下，哌甲酯在约0.1 μM时抑制DAT和NET，而在约100 μM时抑制SERT。安非他明效力的顺序为NET（KI = 0.07-0.1 μM）、DAT（KI = 0.6 μM）和SERT（KI在20 - 40 μM之间）。甲基苯丙胺的结果与苯丙胺相似。相比之下，另一种安非他明衍生物，MDMA（3-4亚甲二氧基甲基安非他明），表现出更高的效力在SERT比在DAT。人类和小鼠的转运体是相似的，他们的敏感性，每一个测试的药物（KI值是在4倍）。目前和以前的研究支持以下结论：1）可卡因在相似浓度下阻断所有3种单胺转运体：2）哌甲酯很好地抑制DAT和NET，但需要1000倍的药物浓度才能抑制SERT; 3）安非他明和甲基安非他明对NET的效力最强，而对DAT的效力低5至9倍，对SERT的效力低200至500倍; 4）MDMA对SERT和NET的表观亲和力略高于DAT。药物抑制DAT、NET和SERT的相对效力表明，这些兴奋剂中的每一种对哪些神经递质系统的破坏最大，因此可能是药物作用的主要机制。
The plasma membrane neurotransmitter transporters terminate neurotransmissions by the reuptake of the released neurotransmitters. The transporters for the monoamines dopamine, norepinephrine, and serotonin (DAT, NET, and SERT) are targets for several popular psychostimulant drugs of abuse. The potencies of the psychostimulant on the monoamine transporters have been studied by several laboratories. However, there are significant discrepancies in the reported data with differences up to 60-fold. In addition, the drug potencies of the 3 monoamine transporters from mouse have not been compared in the same experiments or along side the human transporters. Further studies and systematic comparisons are needed. In this study, we compared the potencies of five psychostimulant drugs to inhibit human and mouse DAT, SERT and NET in the same cellular background. The KI values of cocaine to inhibit the 3 transporters are within a narrow range of 0.2 to 0.7 μM. In comparison, methylphenidate inhibited DAT and NET at around 0.1 μM, while it inhibited SERT at around 100 μM. The order of amphetamine potencies was NET (KI = 0.07–0.1 μM), DAT (KI ≈ 0.6 μM), and SERT (KI between 20 to 40 μM). The results for methamphetamine were similar to those for amphetamine. In contrast, another amphetamine derivative, MDMA (3–4 methylenedioxymethamphetamine), exhibited higher potency at SERT than at DAT. The human and mouse transporters were similar in their sensitivities to each of the tested drugs (KI values are within 4-fold). The current and previous studies support the following conclusions: 1) cocaine blocks all 3 monoamine transporters at similar concentrations; 2) methylphenidate inhibits DAT and NET well but a 1000-fold higher concentration of the drug is required to inhibit SERT; 3) Amphetamine and methamphetamine are most potent at NET, while being 5- to 9-fold less potent at DAT, and 200- to 500-fold less potent at SERT; 4) MDMA has moderately higher apparent affinity for SERT and NET than for DAT. The relative potencies of a drug to inhibit DAT, NET and SERT suggest which neurotransmitter systems are disrupted the most by each of these stimulants and thus the likely primary mechanism of drug action.