The combination of M100907, a putative antipsychotic drug (APD) and serotonin (5-HT)(2A) antagonist, and the typical APD haloperidol, can enhance dopamine (DA) release in rat medial prefrontal cortex (mPFC), an effect which has been postulated to be of value to improve cognition and negative symptoms. The present study demonstrated that another putative APD and 5-HT(2A/2C) antagonist, SR46349-B (10 mg/kg, but not 1-3 mg/kg) alone, but not M100907 (0.1 and 3 mg/kg) alone, increased mPFC DA release, whereas neither drug alone affected nucleus accumbens (NAC) DA release. Neither SR46349-B nor M100907 alone affected nucleus accumbens (NAC) DA release. Neither SR46349-B nor M100907 alone affected nucleus accumbens (NAC) DA release. SR46349-B (3 mg/kg) potentiated haloperidol-induced DA release in both regions, whereas M100907 (0.1 mg/kg) potentiated haloperidol (0.1 mg/kg)-induced mPFC DA release and inhibited it in the NAC. WAY100635 (0.2 mg/kg), a 5-HT(1A) antagonist, abolished the effects of haloperidol plus M100907 as well as SR46349-B on DA release in the mPFC, but did not do so in the NAC. Thus, 5-HT(2A) and 5-HT(2A/2C) antagonism together with haloperidol-induced D(2) antagonism may potentiate mPFC DA release via 5-HT(1A) agonism, whereas the combined effects of these agents on NAC DA release is not dependent upon 5-HT(1A) receptor stimulation. Interestingly, similar to the effect of SR46349-B, high dose M100907 (3 mg/kg), which might have antagonist activity at 5-HT(2C) receptors, potentiated 1 mg/kg haloperidol-induced DA release in the mPFC and NAC. These results suggest that 5-HT(2A/2C) antagonism may be more advantageous than selective 5-HT(2A) antagonism as an adjunct to D(2) antagonists to improve cognition and negative symptoms in schizophrenia.