New light on the serotonergic paradox in the rat circadian system

The main mammalian circadian clock, localized in the suprachiasmatic nuclei can be synchronized not only with light, but also with serotonergic activation. Serotonergic agonists and serotonin reuptake inhibitors (e.g., fluoxetine) have a non-photic influence (shifting effects during daytime and attenuation of photic resetting during nighttime) on hamsters' and mice' main clock. Surprisingly, in rats serotonergic modulation of the clock shows essentially photic-like features in vivo (shifting effects during nighttime). To delineate this apparent paradox, we analyzed the effects of fluoxetine and serotonin agonists on rats' clock. First, fluoxetine induced behavioral phase-advances associated with down-regulated expression of the clock genes Per1 and Rorβ and up-regulated expression of Rev-erbα during daytime. Moreover, fluoxetine produced an attenuation of light-induced phase-advances in association with altered expression of Per1, Per2 and Rorβ during nighttime. Second, we showed that 5-HT₁A receptors -maybe with co-activation of 5-HT₇ receptors- were implicated in non-photic effects on the main clock. By contrast, 5-HT₃ and 5-HT₂C receptors were involved in photic-like effects and, for 5-HT₂C subtype only, in potentiation of photic resetting. Thus this study demonstrates that as for other nocturnal rodents, a global activation of the serotonergic system induces non-photic effects in the rats' clock during daytime and nighttime.