5-HT_1A and 5-HT_2A receptors minimally contribute to clozapine-induced acetylcholine release in rat medial prefrontal cortex

The atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone, and ziprasidone preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC). These effects have been shown to depend upon potent 5-HT_2A relative to weak D₂ antagonism, and 5-HT_1A agonism as well. Atypical APDs also increase acetylcholine (ACh) release in the mPFC, but not the nucleus accumbens (NAC) or striatum (STR), whereas typical APDs such as haloperidol, S(-)-sulpiride and thioridazine do not produce either effect in the mPFC. This study examined the role of 5-HT_1A agonism, 5-HT_2A and D₂ antagonism, and the combination thereof, in the ability of clozapine to increase ACh release in rat mPFC. R(+)-8-OH-DPAT (0.2 mg/kg), a 5-HT_1A agonist, WAY100635 (0.2-0.5 mg/kg), a 5-HT_1A antagonist, and DOI (0.6-2.5 mg/kg), a 5-HT_2A/2C agonist, increased ACh release in the mPFC, whereas M100907 (0.03-1 mg/kg), a 5-HT_2A antagonist, did not. DOI (2.5 mg/kg) and M100907 (0.1 mg/kg) had no effect on ACh release in the NAC or STR. WAY100635 and M100907 inhibited the ability of R(+)-8-OH-DPAT and DOI, respectively, to increase ACh release in the mPFC. WAY100635, which inhibits clozapine-induced DA release in the mPFC, failed to inhibit clozapine (20 mg/kg)-induced ACh release in that region. Similarly, the combination of M100907 and haloperidol (0.1 mg/kg), which enhances DA release in the mPFC, failed to increase ACh release in that region. These results suggest that 5-HT_1A agonism and 5-HT_2A antagonism, as well as DA release, contribute minimally to the ability of clozapine, and perhaps other atypical APDs, to increase ACh release in the mPFC.