SR46349-B, a 5-HT_2A/2C receptor antagonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens

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 D₂ 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 D₂ antagonists to improve cognition and negative symptoms in schizophrenia.