Perospirone, a novel atypical antipsychotic drug, potentiates fluoxetine-induced increases in dopamine levels via multireceptor actions in the rat medial prefrontal cortex.

Perospirone is a novel atypical antipsychotic with a unique combination of 5-HT1A receptor agonism as well as 5-HT2A and D2 receptor antagonism. We investigated the effect of perospirone in combination with fluoxetine on dopamine release in the rat medial prefrontal cortex using microdialysis. Perospirone and fluoxetine increased dopamine release to 270 and 210% of the baseline value, respectively. A combination of perospirone and fluoxetine markedly increased dopamine release to 800% of the baseline value. Pretreatment with a selective 5-HT1A receptor antagonist, WAY 100635, suppressed the increase in dopamine levels induced by the administration of perospirone and fluoxetine to 330% of the baseline value. These findings suggest that perospirone potentiates fluoxetine-induced dopamine increases in part via the action of the 5-HT1A receptor and may augment the effect of fluoxetine in treatment-resistant depression.