Background The 5-hydroxytryptamine 7 receptor (5-HT 7 ) is implicated in circadian rhythm phase resetting, and 5-HT 7 receptor-selective antagonists alter rapid eye movement (REM) sleep parameters in a pattern opposite from those in patients with clinical depression.

Methods As sleep, circadian rhythm, and mood regulation are related, we examined 5-HT 7 receptor knockout mice in two behavioral models of depression. The forced swim and tail suspension tests are highly predictive for antidepressant drug activity.

Results Unmedicated 5-HT 7 −/− mice showed decreased immobility in both tests, consistent with an antidepressantlike behavior. The selective 5-HT 7 receptor antagonist SB-269970 also decreased immobility. The selective serotonin reuptake inhibitor citalopram, a widely used antidepressant, decreased immobility in both 5-HT 7 +/+ and 5-HT 7 −/− mice in the tail suspension test, suggesting that it utilizes an independent mechanism. The 5-HT 7 −/− mice spent less time in and had less frequent episodes of REM sleep, also consistent with an antidepressantlike state.