The 5-HT(7) receptor has been suggested as a target for treating depression since inactivation or blockade of the receptor has an antidepressant-like behavioral effect. The present study investigated possible interactions between various classes of drugs with antidepressant properties and blockade or inactivation of the 5-HT(7) receptor. Immobility despair in the tail suspension test and the forced swim test was evaluated in mice lacking the 5-HT(7) receptor (5-HT(7)(-/-)) and in wild-type controls (5-HT(7)(+/+)) following acute drug treatments. Citalopram, a selective serotonin reuptake inhibitor and widely used antidepressant, dose-dependently reduced immobility in the tail suspension test in both 5-HT(7)(+/+) and 5-HT(7)(-/-) mice. Combining doses of citalopram and the 5-HT(7) receptor antagonist SB-269970 that by themselves did not affect behavior, reduced immobility in 5-HT(7)(+/+) mice in both the tail suspension test and the forced swim test. No effect was seen in 5-HT(7)(-/-) mice. Desipramine and reboxetine, two norepinephrine reuptake inhibitors, dose-dependently reduced immobility in the tail suspension test in 5-HT(7)(+/+) mice, but had no effect in 5-HT(7)(-/-) mice. A synergistic effect between desipramine and SB-269970 was found in both behavioral tests in 5-HT(7)(+/+) mice. Reboxetine combined with SB-269970 had effect only in the forced swim test. GBR 12909, a dopamine reuptake inhibitor, dose-dependently reduced tail suspension test immobility in both genotypes. There was no interaction between GBR 12909 and SB-269970. Aripiprazole, an antipsychotic, reduced immobility in both tests in 5-HT(7)(+/+) mice, but not in 5-HT(7)(-/-) mice. The results show that the 5-HT(7) receptor is required for the observed interaction between this receptor and antidepressants such as citalopram. The data furthermore support the hypothesis that the 5-HT(7) receptor might be a suitable target for treating depression.