Synthetic cathinone derivatives are a new class of psychoactive substances (NPS), also known as "bath salts", designed to exert psychostimulant effects resembling those of well-known psychostimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). As major constituents of bath salts, the cathinone derivatives 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylmethcathinone (mephedrone), have received considerable media attention. MDPV and mephedrone interfere with the function of the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT), resulting in increased extracellular levels of these monoamines, though their mechanism of action differs. MDPV acts as a non-transported inhibitor of DAT, NET and SERT, whereas mephedrone promotes transporter-mediated release in an amphetamine-like fashion. MDPV and mephedrone are often taken together, creating a conundrum in as much as non-transported inhibitors, like MDPV, prevent mephedrone-induced reverse transport via DAT, NET and SERT. Here we provide evidence supporting a role for organic cation transporter 3 (OCT3) in the actions of mephedrone, which may account for its ability to enhance effects of MDPV. We show that mephedrone can induce substrate efflux via OCT3 in the presence of MDPV. Real-time recordings of the fluorescent OCT3 substrate (4-(4-dimethylamino)styryl)-N-methylpyridinium (ASP+) and radiotracer-flux studies using [3H]1-methyl-4-phenyl-pyridinium (MPP+), demonstrated that OCT3 is MDPV-insensitive when expressed in human embryonic kidney (HEK293) cells. Ex vivo experiments performed in cultured superior cervical ganglia (SCG) cells, rich in NET and OCT3, revealed that mephedrone induces [3H]MPP+ release in an OCT3-dependent manner when NET is fully occupied with MDPV. These results extend our recent findings that OCT3 is key in the mechanism of action of amphetamine-induced substrate release. OCT3 likewise appears to be a mechanism through which mephedrone can induce release of monoamines, thereby accounting for the paradoxically more potent psychostimulant effects of MDPV taken together with mephedrone, and greater risk for deleterious side effects.

中文翻译：

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“Polytox”合成卡西酮滥用：有机阳离子转运蛋白 3 在联合卡西酮诱导的外排中的潜在作用。

合成卡西酮衍生物是一类新的精神活性物质 (NPS)，也称为“浴盐”，旨在发挥类似于众所周知的精神兴奋剂的精神兴奋作用，例如可卡因和 3,4-亚甲二氧基甲基苯丙胺（MDMA，“摇头丸” ）。作为浴盐的主要成分，卡西酮衍生物 3,4-亚甲二氧基吡戊酮 (MDPV) 和 4-甲基甲卡西酮 (甲氧麻黄酮) 受到了媒体的广泛关注。MDPV 和甲氧麻黄酮会干扰多巴胺 (DAT)、去甲肾上腺素 (NET) 和血清素 (SERT) 的高亲和力转运蛋白的功能，导致这些单胺的细胞外水平升高，尽管它们的作用机制不同。MDPV 作为 DAT、NET 和 SERT 的非转运抑制剂，而甲氧麻黄酮以类似苯丙胺的方式促进转运蛋白介导的释放。MDPV 和甲氧麻黄酮经常一起服用，这造成了一个难题，就像 MDPV 等非转运抑制剂通过 DAT、NET 和 SERT 阻止甲氧麻黄酮诱导的反向转运一样。在这里，我们提供了支持有机阳离子转运蛋白 3 (OCT3) 在甲氧麻黄酮作用中的作用的证据，这可能解释了其增强 MDPV 作用的能力。我们表明，在 MDPV 存在的情况下，甲氧麻黄酮可以通过 OCT3 诱导底物流出。荧光 OCT3 底物（4-（4-二甲氨基）苯乙烯基）-N-甲基吡啶鎓 (ASP+) 的实时记录和使用 [3H]1-甲基-4-苯基-吡啶鎓 (MPP+) 的放射性示踪剂通量研究表明， OCT3 在人胚胎肾 (HEK293) 细胞中表达时对 MDPV 不敏感。在富含 NET 和 OCT3 的培养的颈上神经节 (SCG) 细胞中进行的离体实验表明，当 NET 完全被 MDPV 占据时，甲氧麻黄酮以 OCT3 依赖性方式诱导 [3H]MPP+ 释放。这些结果扩展了我们最近的发现，即 OCT3 是苯丙胺诱导的底物释放作用机制的关键。OCT3 同样似乎是一种机制，通过该机制，甲氧麻黄酮可以诱导单胺类物质的释放，从而解释了 MDPV 与甲氧麻黄酮一起使用时产生的更强烈的精神兴奋作用，以及更大的有害副作用风险。这些结果扩展了我们最近的发现，即 OCT3 是苯丙胺诱导的底物释放作用机制的关键。OCT3 同样似乎是一种机制，通过该机制，甲氧麻黄酮可以诱导单胺类物质的释放，从而解释了 MDPV 与甲氧麻黄酮一起使用时产生的更强烈的精神兴奋作用，以及更大的有害副作用风险。这些结果扩展了我们最近的发现，即 OCT3 是苯丙胺诱导的底物释放作用机制的关键。OCT3 同样似乎是一种机制，通过该机制，甲氧麻黄酮可以诱导单胺类物质的释放，从而解释了 MDPV 与甲氧麻黄酮一起使用时产生的更强烈的精神兴奋作用，以及更大的有害副作用风险。