5‐HT2A and D2 receptor blockade increases cortical DA release via 5‐HT1A 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‐HT1A 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‐HT1A receptor activation, as a result of the blockade of 5‐HT2A and D2 receptors. M100907 (0.1 mg/kg), a 5‐HT2A antagonist, significantly increased the ability of both S(–)‐sulpiride (10 mg/kg), a D2 antagonist devoid of 5‐HT1A affinity, and R(+)‐8‐OH‐DPAT (0.05 mg/kg), a 5‐HT1A agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5‐HT1A 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‐HT1A partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5‐HT2A and D2 receptor blockade, regardless of intrinsic 5‐HT1A affinity, may promote the ability of 5‐HT1A receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5‐HT2A antagonists and typical APDs, which are D2 antagonists, may facilitate 5‐HT1A agonist activity.