Translational Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
Neuropsychopharmacology. 2012 Apr;37(5):1192-203. doi: 10.1038/npp.2011.304. Epub 2011 Dec 14.
The nonmedical use of 'designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study.
非医疗用途的“设计”卡他碱类似物，如 4-甲基甲卡西酮（Mephedrone）和 3,4-亚甲基二氧甲基卡西酮（Methylone），在全球范围内不断增加，但对于这些药物的作用机制知之甚少。在这里，我们采用体外和体内方法比较了 Mephedrone 和 Methylone 与结构相关化合物 3,4-亚甲基二氧甲基苯丙胺（MDMA）和甲基苯丙胺产生的神经生物学效应。使用大鼠脑突触体的体外释放测定表明，Mephedrone 和 Methylone 是非选择性的血浆膜单胺转运体底物，与 MDMA 的效力和选择性相似。在大鼠伏隔核的体内微透析研究表明，静脉注射 0.3 和 1.0mg/kg 的 Mephedrone 或 Methylone 会导致细胞外多巴胺和 5-羟色胺（5-HT）的剂量相关增加，其对 5-HT 的影响更大。与甲基苯丙胺相比，这两种甲卡西酮类似物都是较弱的运动兴奋剂。重复给予 Mephedrone 或 Methylone（3.0 和 10.0mg/kg，皮下，3 次）会引起体温升高，但不会导致皮质或纹状体胺类物质的长期变化，而类似的 MDMA（2.5 和 7.5mg/kg，皮下，3 次）治疗会引起强烈的体温升高和皮质和纹状体 5-HT 的持续耗竭。我们的数据表明，设计的甲卡西酮类似物是单胺转运体的底物，具有与 MDMA 相当的递质释放活性。Mephedrone 和 Methylone 的多巴胺能效应可能有助于它们的成瘾潜力，但这一假设仍有待证实。鉴于 Mephedrone 和 Methylone 的广泛使用，确定重复药物暴露的后果需要进一步研究。
