Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
Neuropharmacology. 2012 Jun;62(7):2278-87. doi: 10.1016/j.neuropharm.2012.01.024. Epub 2012 Feb 4.
Mirtazapine, an antidepressant, antagonizes α(2)-adrenergic autoreceptors and heteroreceptors, which leads to enhanced noradrenergic and serotonergic transmission without inhibiting monoamine transporters. Using a microdialysis technique, we investigated whether co-administration of mirtazapine and a serotonin noradrenaline reuptake inhibitor (SNRI), milnacipran, augments the effects of each drug on the extracellular levels of monoamines by pharmacological synergy. Mirtazapine increased the extracellular levels of noradrenaline and serotonin in the dorsal hippocampus. In contrast, it increased the levels of noradrenaline and dopamine without changing serotonin levels in the prefrontal cortex. Milnacipran increased the levels of all monoamines evaluated in both areas, and the combined treatment with mirtazapine augmented these changes. The combined treatment with idazoxan, an α(2) adrenoceptor antagonist, and milnacipran also increased all monoamine levels in the prefrontal cortex. Ketanserin, a serotonin 5-HT(2A) receptor antagonist, showed no effect in combination with milnacipran, while SB242084, a 5-HT(2C) receptor antagonist, augmented the effects of milnacipran on the levels of serotonin and dopamine in the prefrontal cortex. These results suggest that combined treatment with mirtazapine and milnacipran augments the extracellular levels of noradrenaline, serotonin and dopamine through the blockade of α(2) adrenoceptors without regional specificity, whereas mirtazapine enhances serotonergic transmission in a region-specific manner. 5-HT(2C) receptor antagonism may also partly contribute to the amplification effects of mirtazapine on serotonin and dopamine levels. These neurochemical changes could play a role in reported advantageous clinical effects in patients treated with an SNRI and mirtazapine.
米氮平是一种抗抑郁药，可拮抗α(2)-肾上腺素能自受体和异受体，从而增强去甲肾上腺素和 5-羟色胺的传递，而不抑制单胺转运体。我们采用微透析技术研究了米氮平与去甲肾上腺素和 5-羟色胺再摄取抑制剂（SNRI）米那普仑联合应用是否通过药物协同作用增强了每种药物对单胺类物质细胞外水平的作用。米氮平增加了背海马区的去甲肾上腺素和 5-羟色胺的细胞外水平。相反，它增加了去甲肾上腺素和多巴胺的水平，而不改变前额叶皮层的 5-羟色胺水平。米那普仑增加了两个区域评估的所有单胺类物质的水平，米氮平和米那普仑联合治疗增强了这些变化。与米那普仑联合应用α(2)肾上腺素能受体拮抗剂伊达唑兰也增加了前额叶皮层的所有单胺类物质的水平。与米那普仑联合应用 5-羟色胺 5-HT(2A)受体拮抗剂酮色林没有效果，而 5-HT(2C)受体拮抗剂 SB242084 则增强了米那普仑对前额叶皮层 5-羟色胺和多巴胺水平的作用。这些结果表明，米氮平和米那普仑联合治疗通过阻断α(2)肾上腺素能受体增强了去甲肾上腺素、5-羟色胺和多巴胺的细胞外水平，而没有区域特异性，而米氮平以区域特异性的方式增强了 5-羟色胺的传递。5-HT(2C)受体拮抗作用也可能部分有助于米氮平对 5-羟色胺和多巴胺水平的放大作用。这些神经化学变化可能在报告的接受 SNRI 和米氮平治疗的患者的有利临床效果中发挥作用。
