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Endogenous depression is often accompanied by alterations in core parameters of circadian rhythms, and antidepressant treatments, including serotonergic drugs, sleep deprivation and exercise, alter circadian phase or period in humans or animal models. Antidepressants may act in part through the circadian system, and behavioral antidepressants through a common serotonergic path to the clock. This review evaluates the evidence from animal models that serotonin (5-HT) mediates phase-shifting effects of behavioral stimuli on circadian rhythms. In rodents, 'exercise' stimulated during the rest phase of the rest-activity cycle induces large phase shifts of circadian rhythms. These shifts can be mimicked by short-term sleep deprivation without intense activity. During wheel running or sleep deprivation, 5-HT release in the suprachiasmatic nucleus (SCN) circadian clock is significantly elevated. Lesions of 5-HT afferents to the SCN attenuate phase shifts or entrainment induced by activity in response to some stimuli (e.g., triazolam injections in hamsters, treadmill running in mice) but not others (e.g., novel wheel confinement in hamsters). Antagonists selective to 5HT1, 2 or 7 receptors do not attenuate shifts induced by wheel running, although 5-HT2/7 antagonists do partially block shifts to saline injections. 5-HT agonists (e.g., 8-OH-DPAT) induce large shifts in vitro, but much smaller shifts in vivo, particularly if administered directly to the SCN. Procedures for inducing 5-HT supersensitivity in vivo result in larger shifts to 8-OH-DPAT. 5-HT stimuli may affect the clock by direct and indirect pathways, particularly through the thalamic intergeniculate leaflet, and the role of these pathways may differ across species. At the level of the SCN, 5-HT likely acts through 5-HT7 receptors on neurons and possibly also glial cells. These receptors may be useful targets for the development of antidepressant drugs. In aggregate, the literature provides mixed support for the hypothesis that exercise or behavioral arousal shift the circadian clock by a 5-HT pathway; the role of indirect pathways, interactions with other transmitters, cellular adaptations to denervation, glial cells, and species differences remain to be more fully clarified. Serotonergic and behavioral stimuli provide an intriguing route to elucidate the circadian clockworks and their possible role in depression.
Mistlberger et al. (Sat,) studied this question.