A combination of mirtazapine and milnacipran augments the extracellular levels of monoamines in the rat brain

作者：Yamauchi Miki^*; Imanishi Taiichiro; Koyama Tsukasa

来源：Neuropharmacology, 2012, 62(7): 2278-2287.

DOI：10.1016/j.neuropharm.2012.01.024

• Mirtazapine
• Milnacipran
• Microdialysis
• Noradrenaline
• Serotonin
• Dopamine

Mirtazapine, an antidepressant, antagonizes alpha(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 alpha(2) adrenoceptor antagonist, and milnacipran also increased all monoamine levels in the prefrontal cortex. Ketanserin, a serotonin 5-HT2A receptor antagonist, showed no effect in combination with milnacipran, while SB242084, a 5-HT2C 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 alpha(2) adrenoceptors without regional specificity, whereas mirtazapine enhances serotonergic transmission in a region-specific manner. 5-HT2C 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.

• 出版日期2012-6