Riegert Céline, Wedekind Franziska, Hamida Sami Ben, Rutz Susanne, Rothmaier Anna Katharina, Jones Byron C, Cassel Jean-Christophe, Jackisch Rolf
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der Universität Freiburg, Neuropharmakologisches Labor, Freiburg, Germany.
Int J Neuropsychopharmacol. 2008 Sep;11(6):743-63. doi: 10.1017/S1461145708008481. Epub 2008 Feb 4.
Ethanol (EtOH) potentiates the locomotor effects of 3,4-methylenedioxymetamphetamine (MDMA) in rats. This potentiation might involve pharmacokinetic and/or pharmacodynamic mechanisms. We explored whether the latter could be local. Using a slice superfusion approach, we assessed the effects of MDMA (0.3, 3microm) and/or EtOH (2mm) on the spontaneous outflow and electrically evoked release of serotonin (5-HT), dopamine (DA) and acetylcholine (ACh) in the striatum, and for comparison, on 5-HT release in hippocampal and neocortical tissue. MDMA and less effectively EtOH, augmented the outflow of 5-HT in all regions. The electrically evoked 5-HT release was increased by MDMA at 3microm in striatal slices only. With nomifensine throughout, EtOH significantly potentiated the 0.3microm MDMA-induced outflow of 5-HT, but only in striatal slices. EtOH or MDMA also enhanced the spontaneous outflow of DA, but MDMA reduced the electrically evoked DA release. With fluvoxamine throughout superfusion, EtOH potentiated the effect of MDMA on the spontaneous outflow of DA. Finally, 3microm MDMA diminished the electrically evoked release of ACh, an effect involving several receptors (D2, 5-HT2, NMDA, nicotinic, NK1), with some interactions with EtOH. Among other results, we show for the first time a local synergistic interaction of EtOH and MDMA on the spontaneous outflow of striatal DA and 5-HT, which could be relevant to the EtOH-induced potentiation of hyperlocomotion in MDMA-treated rats. These data do not preclude the contribution of other pharmacodynamic and/or pharmacokinetic mechanisms in vivo but support the hypothesis that EtOH may affect the abuse liability of MDMA.
乙醇（EtOH）可增强大鼠体内3,4-亚甲基二氧甲基苯丙胺（MDMA）的运动效应。这种增强作用可能涉及药代动力学和/或药效学机制。我们探究了后者是否可能具有局部性。采用脑片灌流法，我们评估了MDMA（0.3、3微摩尔）和/或EtOH（2毫摩尔）对纹状体中5-羟色胺（5-HT）、多巴胺（DA）和乙酰胆碱（ACh）的自发释放及电刺激诱发释放的影响，作为对照，还评估了其对海马体和新皮质组织中5-HT释放的影响。MDMA以及效果稍弱的EtOH，均增加了所有区域5-HT的释放。仅在纹状体脑片中，3微摩尔的MDMA增加了电刺激诱发的5-HT释放。全程使用诺米芬辛时，EtOH显著增强了0.3微摩尔MDMA诱导的5-HT释放，但仅在纹状体脑片中如此。EtOH或MDMA也增强了DA的自发释放，但MDMA减少了电刺激诱发的DA释放。全程使用氟伏沙明灌流时，EtOH增强了MDMA对DA自发释放的作用。最后，3微摩尔的MDMA减少了电刺激诱发的ACh释放，该效应涉及多种受体（D2、5-HT2、NMDA、烟碱型、NK1），且与EtOH存在一些相互作用。在其他结果中，我们首次展示了EtOH和MDMA对纹状体DA和5-HT自发释放存在局部协同相互作用，这可能与EtOH诱导MDMA处理的大鼠出现运动亢进增强有关。这些数据并不排除体内其他药效学和/或药代动力学机制的作用，但支持了EtOH可能影响MDMA滥用倾向的假说。
