Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
Eur J Pharmacol. 2018 Oct 15;837:72-80. doi: 10.1016/j.ejphar.2018.08.037. Epub 2018 Aug 30.
The addiction-related behavioural effects of drugs of abuse are mediated by the mesocorticolimbic monoamine systems. We investigated the effects of 3,4-methylenedioxymethamphetamine (MDMA), mephedrone, β-phenylethylamine (β-PEA) methylphenidate (MPH) on dopamine release from mouse perfused nucleus accumbens and prefrontal cortex slices. The fractional release of [H]-dopamine was measured at rest and in response to field stimulation. The distributions of [H]-dopamine and its metabolites were determined using high-pressure liquid chromatography. The effect of drugs on [H]-dopamine uptake was measured in synaptosomal P2 preparations from the frontal cortex and striatum. Similar to MDMA, mephedrone β-PEA increased the resting release of [H]-dopamine from the nucleus accumbens and prefrontal cortex in a [Ca]-independent manner, and the stimulation-evoked release was also augmented. In contrast, MPH failed to affect the resting release but potentiated the release in response to axonal activity. Similar to dopamine transporter antagonist GBR 12909, mephedrone, MDMA and MPH biphasically inhibited the [H]-dopamine uptake. The administration of GBR 12909 and nisoxetine, or lowering the bath temperature prevented MDMA, mephedrone and β-PEA from enhancing the resting, cytoplasmic release of [H]-dopamine, indicating the role of transporters in the release process. We conclude that amphetamine-like drugs of abuse and the trace amine β-PEA excessively increase the [Ca]-independent, non-vesicular release of dopamine from the cytoplasm into the extrasynaptic space and inhibit the high-affinity transporters, thereby maintaining a high ambient, non-synaptic concentration of dopamine that may tonically control the activity of neurons equipped with dopamine receptors and is likely involved in the reinforcing effects and abusive potential of amphetamines.
滥用药物的成瘾相关行为效应是由中脑边缘单胺系统介导的。我们研究了 3,4-亚甲二氧基甲基苯丙胺（MDMA）、 甲卡西酮、β-苯乙胺（β-PEA）和哌甲酯（MPH）对小鼠灌流伏隔核和前额叶皮层切片多巴胺释放的影响。[H]-多巴胺的分数释放在静息状态和场刺激下进行测量。使用高压液相色谱法测定[H]-多巴胺及其代谢物的分布。在来自前额叶皮层和纹状体的突触小体 P2 制剂中测量药物对[H]-多巴胺摄取的影响。与 MDMA 类似，甲卡西酮、β-PEA 以[Ca]2+非依赖性方式增加伏隔核和前额叶皮层中[H]-多巴胺的静息释放，刺激诱发的释放也增强。相比之下，MPH 未能影响静息释放，但增强了对轴突活动的反应释放。与多巴胺转运体拮抗剂 GBR 12909 类似，甲卡西酮、MDMA 和 MPH 呈双相抑制[H]-多巴胺摄取。GBR 12909 和奈西丁的给药或降低浴温可防止 MDMA、甲卡西酮和β-PEA 增强[H]-多巴胺的静息、细胞质释放，表明转运体在释放过程中的作用。我们的结论是，安非他命样滥用药物和痕量胺β-PEA 过度增加了细胞质中[Ca]2+非依赖性、非囊泡的多巴胺释放到细胞外间隙，并抑制了高亲和力转运体，从而维持了高背景、非突触多巴胺浓度，可能对具有多巴胺受体的神经元的活动进行紧张性控制，并且可能与安非他命的强化作用和滥用潜力有关。
