Mirtazapine in combination with perospirone synergistically enhances dopamine release in the rat prefrontal cortex via 5-HT1A receptor activation

Aims: The purpose of this study was to elucidate the mechanism underlying the clinical efficacy of mirtazapine–perospirone combination therapy for treatment‐resistant depression in a rat model. Methods: We studied the effect of combination therapy of the noradrenergic and specific serotonergic antidepressant mirtazapine and the serotonin‐dopamine antagonist perospirone on serotonin (5‐HT) and dopamine release in the rat medial prefrontal cortex (mPFC) by using microdialysis. Male Wistar rats (250–330 g bodyweight) underwent implantation of a guide cannula in the mPFC, and a microdialysis probe was then inserted into the guide cannula to ensure its final placement in the mPFC. Microdialysis and subsequent chromatographic analysis were performed to estimate the extracellular 5‐HT and dopamine concentrations. Results: When they were used individually, perospirone (0.25 mg/kg, intraperitoneally) and mirtazapine (4 mg/kg, intraperitoneally) induced increased dopamine release up to 134% and 190% relative to the pretreatment level, respectively. Their combination therapy synergistically and significantly (P < 0.0001) increased the dopamine concentration up to 397% of the pretreatment level compared with that induced by the individual drugs. This combination‐induced dopamine release was attenuated by 5‐HT_1A antagonist WAY 100635 (0.5 mg/kg, intraperitoneally), to a peak dopamine release of 151%. Extracellular 5‐HT release in the mPFC was not altered in any of the treatment groups. Conclusions: The large increase in the dopamine concentration in the rat mPFC after the combination therapy was unique and may be responsible for the profound antidepressive effect observed in patients with treatment‐resistant depression.