Decreased activity of the prefrontal cortex (PFC), as well as reduced serotonergic neurotransmission, is considered as a characteristic feature of major depression. The mechanism by which electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) achieve their antidepressant effects may involve changes in PFC activity. It is, however, still unclear whether these changes are accompanied by increased synaptic availability of serotonin (5-HT). In the present study, 5-HT efflux in the rat ventral hippocampus and amygdala was analyzed using in vivo microdialysis during low-current electrical stimulation of PFC and other cortical regions. Electrical stimulation of the medial PFC produced current-dependent increases in limbic 5-HT output in both urethane-anesthetized and behaving rats. No effects on 5-HT levels were seen after comparable stimulation of either the lateral parts of the PFCAn extensive body of clinical evidence suggests that prefrontal cortex (PFC) abnormalities are involved in the pathophysiology of major depression. Significantly decreased cerebral blood flow as well as reduced rates of glucose metabolism have been consistently found in the PFC of depressed patients (Soares and Mann 1997;Kennedy et al. 1997;George et al. 1993). This reduction seems to be localized predominantly in the left hemisphere (Baxter et al. 1989;Martinot et al. 1990). This is supported by structural neuroimaging studies demonstrating that poststroke depression is more likely to occur following a lesion in the left PFC rather than either in the right PFC or elsewhere in the left hemisphere (Morris et al. 1996;Robinson et al. 1984). Both neuropsychological and oculomotor functioning of prefrontal cortex is impaired in depression (Goodwin 1997;Sweeney et al. 1998). Furthermore, symptom improvement and remission of depressed patients have been associated with increases in cerebral blood flow and glucose metabolism in this region (Goodwin et al. 1993;Bench et al. 1995;Bonne and Krausz 1997;Buchsbaum et al. 1997 NO . 3 This close association between prefrontal cortical dysfunction and depression suggests that enhancement of PFC activity might be beneficial in the treatment of this disorder. Consistent with this idea, electroconvulsive therapy (ECT), as well as transcranial magnetic stimulation (TMS), seems to achieve its antidepressant effects by altering PFC activity. ECT leads to pronounced prefrontal EEG changes, which are directly related to the therapeutic outcome. Hence, the efficacy of ECT seems to be critically linked to prefrontal cortex involvement in ECT-induced seizure activity (Sackeim et al. 1996). This is further supported by studies that have reported changes in cerebral blood flow in prefrontal cortex of ECT responders (Nobler et al. 1994;Bonne et al. 1996;Petracca et al. 1995). In recent years, repetitive TMS of the left dorsolateral prefrontal cortex has emerged as a successful antidepressant treatment (Pascual-Leone et al. 1996;George et al. 1997). Although the exact mechanism underlying the ef...