5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern

Background: The 5-hydroxytryptamine(7) receptor (5-HT7) is implacted in circadian rhythm phase resetting, and 5-HT7 receptor-selective antagonists alter rapid eye movement (REM) sleep parameter in a pattern opposite from those in patients with clinical depression. Methods: As sleep, circadian rhythm, and mood regulation are related, we exmained 5-HT7 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-HT7-/- mice showed decreased immobility in both tests, consistent with an antidepressantlike behavior. The selective 5-HT7 receptor antagonist SB-269970 also decreased immobility. The selective serotonin reuptake inhibitor citalopram, a widely used antidepresant, decreased immobility in both 5-HT7+/+ and 5-HT7-/- mice in the tail suspension test, suggesting that it utilizes an independent mechanism. The 5-HT7-/- mice spent less time in and had less frequent episodes of REM sleep, also consistent with an antidepressantlike state. Conclusions: The 5-HT7 receptor might have a role in mood disorders and antagonists might have therapeutic value as antidepresants.