The selective 5-HT2A receptor antagonist, MDL 100,907, increases dopamine efflux in the prefrontal cortex of the rat

Diminished function within the mesocortical dopamine system has been to hypothesized to contribute directly to the negative and indirectly to the positive symptoms of schizophrenia. Based on the proposed role of 5-HT2 receptor blockade in the antipsychotic profile of clozapine and its preferential augmentation of prefrontal dopamine release, we have examined the effects of the selective 5-HT2A receptor antagonist, R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidi ne- methanol (MDL 100,907), on dopamine release in the rat medial prefrontal cortex using in vivo microdialysis. The results indicate that local 5-HT2A receptors exert a tonic inhibitory influence on dopamine efflux in the medial prefrontal cortex. These observations are consistent with the hypothesis that 5-HT2A receptor blockade contributes to the unique antipsychotic profile of clozapine and that MDL 100,907 may have antipsychotic activity.