The pharmacological and physiological effects of chronic administration of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI) fluoxetine and the dual 5-HT/norepinephrine (NE) reuptake inhibitor duloxetine were compared on 5-HT-mediated electrophysiological responses recorded in the hippocampus of young (3-5 months) and old (17-20 months) female Fischer 344 rats. Fluoxetine, duloxetine, or vehicle (saline) was administered once daily for 14 days (10 mg/kg, i.p.) and extracellular recordings of spontaneously firing CA1 and CA3 pyramidal neurons were conducted 24 h following the last injection using microiontophoretic drug application techniques in a chloral hydrate anesthetized preparation. The recovery times (RT50 values; sec) following 5-HT application on pyramidal neurons were significantly increased in the young and old chronic fluoxetine (FLX) treated groups (73% and 104%, respectively; P < 0.05), but not chronic duloxetine- (DLX) or vehicle- (VEH) treated groups. Following prolonged application of duloxetine (5-10 min), the 5-HT RT50 values were significantly increased in the young FLX groups as compared to the age-matched DLX- and VEH-treated groups. In contrast, a significant decline in the time to recovery produced by 5-HT (52%) was observed in the old vs. young FLX-treated group following the second co-application of 5-HT with duloxetine. Within each drug treatment and age group, co-application of duloxetine and 5-HT did not alter the inhibitory responses (IT50 values; nC) produced by the application of 5-HT alone. These results demonstrate cellular adaptive changes in serotonergic neuronal function occur following repeated exposure to 5-HT reuptake inhibitors in an age-dependent manner.