The present study examined the effect of zotepine, an atypical antipsychotic, on the in vivo release of monoamines in the prefrontal cortex of rats using microdialysis. Local perfusion of zotepine at 10 microM increased extracellular levels of serotonin (5-HT), as well as dopamine and noradrenaline, in the prefrontal cortex. However, systemic administration of zotepine did not affect 5-HT release, although it increased the dopamine and noradrenaline release. These results suggest that the prefrontal 5-HT system does not contribute to the antidepressant effect of zotepine. The difference in the effect of zotepine between local and systemic treatment is discussed.