5-HT(7) receptors are involved in REM sleep and possibly in mood disorders. REM sleep suppression and antidepressant-like behavior is observed in 5-HT(7)(-/-) mice and in rats treated with 5-HT(7) receptor antagonists. We recently demonstrated that pharmacological blockade of 5-HT(7) receptors enhances REM sleep suppression and antidepressant-like behavior induced by citalopram in rodents. It has been hypothesized that the effect of citalopram on sleep is essentially mediated by the activation of 5-HT(1A) receptors. The present study investigates the impact of 5-HT(7) receptor gene deletion on the effect of various reuptake inhibitors on REM sleep and probes the role of 5-HT(1A) receptors in this response. Three SSRIs (citalopram, fluoxetine and paroxetine) but not the tricyclic antidepressant desipramine had a significantly stronger REM sleep suppressive effect in 5-HT(7)(-/-) mice compared to 5-HT(7)(+/+) mice. In contrast, REM sleep was similarly reduced in 5-HT(7)(+/+) mice and 5-HT(7)(-/-) mice after treatment with the 5-HT(1A) receptor agonist ipsapirone. Furthermore, both 5-HT(7)(+/+) and 5-HT(7)(-/-) mice displayed the same increase in REM sleep duration produced by the 5-HT(1A) receptor antagonist WAY-100635. These findings indicate that 5-HT(7) receptor deletion augments the effect of various SSRIs on REM sleep suppression and that this effect is distinct from those mediated via 5-HT(1A) receptors.