5-HT2A and D-2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-inducedcortical dopamine release

Atypical antipsychotic drugs (APDs), all of which are relatively more poten t as serotonin (5-HT)(2A) than dopamine D-2 antagonists, may improve negati ve symptoms and cognitive dysfunction in schizophrenia, in part, via increa sing cortical dopamine release. 5-HT1A agonism has been also suggested to c ontribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and p erhaps other atypical APDs, increase dopamine release in rat medial prefron tal cortex (mPFC) via 5-HT1A receptor activation, as a result of the blocka de of 5-HT2A and Dg receptors. M100907 (0.1 mg/ kg), a 5-HT2A antagonist, s ignificantly increased the ability of both S(-)-sulpiride (10 mg/kg), a D-2 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 its elf has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reve rsed 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 re lease. Clozapine is a direct acting 5-HT1A partial agonist, whereas olanzap ine and risperidone are not. These results suggest that the atypical APDs v ia 5-HT2A and Dp receptor blockade, regardless of intrinsic 5-HT1A affinity , may promote the ability of 5-HT1A receptor stimulation to increase mPFC D A release, and provide additional evidence that coadministration of 5-HT2A antagonists and typical APDs, which are Dp antagonists, may facilitate 5-HT 1A agonist activity.