5-HT_2A and D₂ receptor blockade increases cortical DA release via 5-HT_1A receptor activation: A possible mechanism of atypical antipsychotic-induced cortical dopamine release

Atypical antipsychotic drugs (APDs), all of which are relatively more potent as serotonin (5-HT)_2A than dopamine D₂ antagonists, may improve negative symptoms and cognitive, dysfunction in schizophrenia, in part, via increasing cortical dopamine release. 5-HT_1A agonism has been also suggested to contribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and perhaps other atypical APDs, increase dopamine release in rat medial prefrontal cortex (mPFC) via 5-HT_1A receptor activation, as a result of the blockade of 5-HT_2A and D₂ receptors. M100907 (0.1 mg/kg), a 5-HT_2A antagonist, significantly increased the ability of both S(-)-sulpiride (10 mg/kg), a D₂ antagonist devoid of 5-HT_1A affinity, and R(+)-8-OH-DPAT (0.05 mg/kg), a 5-HT_1A agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5-HT_1A antagonist, which by itself has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reversed the ability of clozapine (20 mg/kg), olanzapine (1 mg/kg), risperidone (1 mg/kg), and the R(+)-8-OH-DPAT (0.2 mg/kg) to increase mPFC dopamine release. Clozapine is a direct acting 5-HT_1A partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5-HT_2A and D₂ receptor blockade, regardless of intrinsic 5-HT_1A affinity, may promote the ability of 5-HT_1A receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5-HT_2A antagonists and typical APDs, which are D₂ antagonists, may facilitate 5-HT_1A agonist activity.