The present study investigated the effects of various classes of antidepressant drugs (10 mg/kg per day, s.c. during 21 days) on the electrically evoked release of [3H]noradrenaline and on its modulation by the 5-HT3 receptor agonist 2-methyl-5-hydroxy-tryptamine (2-methyl-5-HT) using preloaded rat hippocampal slices. Treatments with either fluoxetine, a selective serotonin (5-HT) reuptake inhibitor, or moclobemide, a reversible type A monoamine oxidase inhibitor, increased the evoked release of [3H]noradrenaline. These two antidepressant treatments did not change, however, the magnitude of the enhancing effect of 2-methyl-5-HT on the electrically evoked release of [3H]noradrenaline. Desipramine produced a much larger increase of the electrically evoked release of [3H]noradrenaline than fluoxetine or moclobemide, and desensitized the 5-HT3 receptors that modulate this release. Trimipramine, which like desipramine has a tricyclic structure but does not block the reuptake of noradrenaline or that of 5-HT, did not increase the evoked release of [3H]noradrenaline and did not desensitize the 5-HT3 receptors that enhance the release of [3H]noradrenaline. Maprotiline, a selective noradrenaline reuptake inhibitor, did not produce the same changes as desipramine, but maprotiline inhibited noradrenaline reuptake to a lesser extent (50%) than desipramine (80%). These results suggest that the high potency noradrenaline reuptake blocker desipramine desensitizes 5-HT3 receptors modulating [3H]noradrenaline release, but that this effect is not common to all antidepressant drugs.