The sensitivity of rostral and cingulate cortical neurons to microiontophoretically administered serotonin (5-HT) was compared in groups of rats treated either acutely or chronically for different periods with various drugs. The drugs used were: desipramine (10 mg/kg), clomipramine (10 mg/kg), CGP 6085 (10 mg/kg), clorgyline (0.3 mg/kg), and deprenyl (1 mg/kg). Serotonin and, in some instances, gamma-aminobutyric acid (GABA) were applied microiontophoretically over periods of 60 sec with various ejection currents to spontaneously active neurons in the rostral and cingulate cortex. Of all the compounds tested, only clorgyline produced a marked desensitization to 5-HT in both cortical areas. After prolonged treatment with all the other drugs, no change in the sensitivity to serotonin was observed. The desensitization to 5-HT induced by clorgyline developed after 4 to 10 days of treatment. The responsiveness of these cells to GABA was unchanged after chronic exposure to clorgyline. The present results are consistent with those biochemical studies showing that chronic treatment with 5-HT-uptake-blocking compounds has no effect on 5-HT-binding characteristics, as well as with the observation that prolonged treatment with the monoamine-oxidase A-type blocker clorgyline reduces the number of 5-HT-binding sites.