Effects of the co-administration of mirtazapine and paroxetine on serotonergic neurotransmission in the rat brain

The alpha-adrenoreceptor antagonist mirtazapine, which is also a 5-HT2, 5-HT3 and H-1 receptors antagonist and the selective serotonin (5-HT) reuptake inhibitor paroxetine are effective antidepressant drugs which enhance 5-HT neurotransmission via different mechanisms. The present studies were undertaken to determine whether the mirtazapine-paroxetine combination could induce an earlier and/or a greater effect on the 5-HT system than either drug alone. Using in vivo electrophysiological paradigms, the firing activity of dorsal raphe 5-HT neurons was decreased by 70% in rats treated with paroxetine (10 mg/kg/day, s.c.) for 2 days and was back to normal after 21 days. In contrast, a 2-day treatment with mirtazapine (5 mg/kg/day, s.c.) did not alter the firing of 5-HT neurons whereas it was increased by 60% after 21 days of treatment. A low dose of mirtazapine (5 mg/kg/day, s.c.x2 days) failed to offset the decremental effect of paroxetine on the 5-HT neuron firing activity, bur a higher dose (10 mg/kg/day, s.c.x2 days) did attenuate the decremental effect of paroxetine. In the dorsal hippocampus, neither mirtazapine (5 mg/kg/day, s.c.) nor a paroxetine (10 mg/kg/day, s.c.) treatment altered the responsiveness of 5-MT1A receptors to microiontophoretically-applied 5-HT. Both in controls and in rats treated for 2 days with paroxetine alone, the administration of the 5-HT1A antagonist WAY 100635 (25-100 mu g/kg, i.v.) did not change the firing activity of dorsal hippocampus CA(3) pyramidal neurons. However, WAY 100635 increased significantly the firing activity of these neurons in rats treated with mirtazapine atone but to a greater extent with both mirtazapine and paroxetine for 2 days. After 21 days of treatment, WAY 100635 increased to a greater degree the firing rate of CA(3) pyramidal neurons in rats which received the combination over rats given either drug alone. It is concluded that the mirtazapine-paroxetine combination shortened the delay in enhancing the tonic activation of postsynaptic 5-HT1A receptors and produced a greater activation of the postsynaptic 5-HT1A receptors than either drug given alone. The present results suggested that mirtazapine may have a faster onset of action than a SSRI, and that the co-administration of mirtazapine and paroxetine may accelerate the antidepressant response and as well as being more effective than either drug alone. (C) 2000 Elsevier Science B.V. All rights reserved.