Trazodone increases extracellular serotonin levels in the frontal cortex of rats

The effects of the antidepressant drug, trazodone, on the extracellular 5-hydroxytryptamine (5-HT) levels in the frontal cortex of freely moving rats was investigated using microdialysis coupled to a high performance liquid chromatography (HPLC) detection method. Systemic administration of 1.25 and 2.5 mg/kg s.c. of trazodone was followed by a rise in the 5-HT level which reached a 5-fold peak over the basal level 5 h after injection, and a 3-fold peak after 1 h. Higher doses had no effect. The increase was prevented by pretreatment with fluoxetine (10 mg/kg s.c.), a 5-HT uptake inhibitor. Direct administration of trazodone (0.03, 0.1, 1, 2 microg/microl), by reverse dialysis into the frontal cortex, elicited a dose-dependent large increase in 5-HT levels. The increase was not prevented by systemic fluoxetine administration but was reduced by local perfusion of ketanserin (0.1 microg/microl) a 5-HT(2A/C) receptor antagonist. Trazodone s.c. administration for 7 days did not increase 5-HT basal levels but enhanced the effects of challenge doses of 2.5 and 5 mg/kg s.c. The present work demonstrated that trazodone increases the 5-HT extracellular level through a double mechanism which involves the 5-HT transporter and 5-HT(2A/C) receptors. This increase may trigger the chain of events which lead to the therapeutic effects, similar to the case of many other antidepressant drugs.