Weikop Pia, Kehr Jan, Scheel-Krüger Jørgen
NeuroSearch A/S, Ballerup, Denmark.
J Psychopharmacol. 2007 Nov;21(8):795-804. doi: 10.1177/0269881107077347.
The purpose of the present study was to examine, by in vivo microdialysis technique, the effects of triple acting monoamine reuptake inhibitors, constructed by combinations of a selective serotonin reuptake inhibitor citalopram with a noradrenaline/dopamine reuptake inhibitor methylphenidate and a serotonin/noradrenaline reuptake inhibitor venlafaxine with a dopamine reuptake inhibitor GBR12909, on extracellular levels of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) in the prefrontal cortex (PFC) of anaesthetized rats. At the highest dose tested, adjunctive methylphenidate (10 mg/kg s.c.) to citalopram markedly attenuated by 63% the extracellular levels of 5-HT as compared to the levels induced by citalopram (5 mg/kg i.p.) alone, whereas the overall DA concentrations significantly increased to about 149% of those induced by methylphenidate alone. Similarly, the combination of venlafaxine with GBR12909 (10 mg/kg s.c.) caused a reduction of 5-HT levels to 66% of the levels induced by venlafaxine (10 mg/kg i.p.) alone, whereas the overall DA levels increased to 151% of the venlafaxine-treated group. The extracellular levels of NA were only marginally affected by the treatments with combined reuptake inhibitors compared to the effects induced by methylphenidate or venlafaxine alone. The modulatory effects of combined administration of the DA/NA reuptake inhibitors with the 5-HT reuptake inhibitors (citalopram and venlafaxine) on potentiation of DA and attenuation of 5-HT efflux were completely reversed by a pre-treatment with the 5-HT(1A) receptor antagonist WAY-100635. These findings suggest a crucial role played by the 5-HT(1A) receptors in balancing the reuptake inhibitory efficacy for the enhancement of 5-HT and DA transmission in the PFC by the drugs combining the reuptake inhibition of all three monoamines.
本研究的目的是通过体内微透析技术，研究由选择性5-羟色胺再摄取抑制剂西酞普兰与去甲肾上腺素/多巴胺再摄取抑制剂哌甲酯组合构建的三重作用单胺再摄取抑制剂，以及由5-羟色胺/去甲肾上腺素再摄取抑制剂文拉法辛与多巴胺再摄取抑制剂GBR12909组合构建的三重作用单胺再摄取抑制剂，对麻醉大鼠前额叶皮质（PFC）细胞外5-羟色胺（5-HT）、去甲肾上腺素（NA）和多巴胺（DA）水平的影响。在测试的最高剂量下，与单独使用西酞普兰（5 mg/kg腹腔注射）相比，联合使用哌甲酯（10 mg/kg皮下注射）辅助西酞普兰可使细胞外5-HT水平显著降低63%，而总的DA浓度显著增加至单独使用哌甲酯所诱导浓度的约149%。同样，文拉法辛与GBR12909（10 mg/kg皮下注射）联合使用可使5-HT水平降至单独使用文拉法辛（10 mg/kg腹腔注射）所诱导水平的66%，而总的DA水平增加至文拉法辛治疗组的151%。与单独使用哌甲酯或文拉法辛相比，联合再摄取抑制剂治疗对NA细胞外水平的影响微乎其微。DA/NA再摄取抑制剂与5-HT再摄取抑制剂（西酞普兰和文拉法辛）联合给药对DA增强和5-HT流出减弱的调节作用，可通过用5-HT(1A)受体拮抗剂WAY-100635预处理完全逆转。这些发现表明，5-HT(1A)受体在平衡联合抑制所有三种单胺再摄取的药物对PFC中5-HT和DA传递增强的再摄取抑制功效方面发挥着关键作用。
