5-HT(2A) receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner.

Combined serotonin (5-HT)(2A) and dopamine (DA) D(2) blockade has been shown to contribute to the ability of atypical antipsychotic drugs (APDs) to increase DA release in rat medial prefrontal cortex (mPFC). We provide additional support for this hypothesis by examining the effect of the selective 5-HT(2A) antagonist M100907 plus haloperidol, a potent D(2) antagonist APD, on DA release in the mPFC and nucleus accumbens (NAC). Haloperidol (0.01-1.0 mg/kg) produced an inverted U-shaped increase in DA release in the mPFC, with a significant increase only at 0.1 mg/kg. Haloperidol (0.1 and 1.0 mg/kg) significantly increased DA release in the NAC. M100907 (0.1 mg/kg) by itself had no effect on DA release in either region. This dose of M100907 potentiated the ability of low (0.01-0.1 mg/kg), but not high dose (0.3-1.0 mg/kg) haloperidol to increase mPFC DA release, whereas it abolished the effect of both 0.1 and 1.0 mg/kg haloperidol on NAC DA release. These results suggest that the relatively higher ratio of 5-HT(2A) to D(2) antagonism may contribute to the potentiation of haloperidol-induced mPFC DA release, whereas 5-HT(2A) antagonism can diminish haloperidol-induced NAC DA release, even when combined with extensive D(2) antagonism, which may not be synergistic with 5-HT(2A) antagonism in the mPFC.