5-HT4 receptors do not mediate the antidepressant-like behavioral effects of fluoxetine in a modified forced swim test

The receptors responsible for mediating the antidepressant effects of selective serotonin reuptake inhibitors are largely unknown. The role of the 5-HT4 receptor in mediating the antidepressant-like effects of fluoxetine in a modified rat forced swim test was examined. Fluoxetine (20 mg/kg) decreased immobility and increased swimming, a pattern shown to represent its actions on the serotonergic system. The selective 5-HT4 receptor antagonist, SB 204070A [8-amino-7-chloro-(N-butyl-4-piperidyl)methylbenzo-1, 4-dioxan-5-carboxylate hydrochloride] (0.1-3 mg/kg), failed to change any of the active behaviors in the test compared with saline-treated animals. Upon combination, SB 204070A (3 mg/kg) failed to alter the effects of fluoxetine effects in the test. These data therefore suggest that activation of postsynaptic 5-HT4 receptors, subsequent to reuptake inhibition by fluoxetine, is not necessary for its antidepressant-like behavioral effects in this test.