Given that norepinephrine (NE) and serotonin (5-HT) neurons are implicated in the mechanisms of action of antidepressant drugs and both project to the hippocampus, the impact of acute and long-term administration of the selective NE inhibitor reboxetine was assessed on CA(3) pyramidal neuron firing in this postsynaptic structure. Cumulative injections of reboxetine (1-4 mg/kg, i.v.) dose-dependently increased the recovery time of the firing of these neurons following iontophoretic applications of NE, but not 5-HT. In rats treated with reboxetine for 2.5 mg/kg/day for 21 days, a robust increase in the recovery time following NE applications was observed, and a small but significant prolongation occurred following 5-HT applications. In controls and reboxetine-treated rats, 1 and 5 Hz stimulations of the afferent 5-HT bundle to the hippocampus, which allows determination of terminal 5-HT(1B) autoreceptor sensitivity, produced similar frequency-dependent decreases in pyramidal neuron firing in both groups. However, after low and high doses of clonidine (10 and 400 microg/kg, i.v.), which assesses alpha(2)-adrenergic auto- and heteroreceptor sensitivity, respectively, only the effect of the high dose of clonidine was attenuated. Interestingly, administration of the selective 5-HT(1A) receptor antagonist WAY 100,635 induced a 140% increase in basal pyramidal neuron firing in reboxetine as compared to saline-treated rats. This increase in tonic activation of postsynaptic 5-HT(1A) receptors might be attributable in part to a desensitization of alpha(2)-adrenergic heteroreceptors, presumably resulting from sustained NE reuptake inhibition. These results indicate that even a selective NE reuptake inhibitor can modulate 5-HT transmission.