Serotonergic actions and interactions on the SCN circadian pacemaker: In vitro investigations

The phase of the mammalian circadian pacemaker located in the suprachiasmat ic nuclei (SCN) is controlled by a multitude of stimuli. While phase contro l is undoubtedly dominated by photic input, the serotonergic input from the raphe nuclei also influences SCN clock phase. In this article I review the evidence for serotonergic modulation of the SCN pacemaker, and the cellula r mechanisms underlying these effects, obtained from in vitro experiments p erformed during the past decade. Serotonin can advance the SCN pacemaker wh en applied during the subjective day, and delay the pacemaker when applied during the subjective night. The daytime advances appear due to stimulation of 5HT(7) receptors, activation of adenylate cyclase and protein kinase A, and opening of K+ channels. The synthesis of new proteins may also be crit ical for these phase shifts. Serotonergic phase advances can be inhibited b y a variety of other modulatory inputs to the SCN, including neuropeptide Y , melatonin, and glutamate. Together, these data demonstrate that SCN circa dian pacemaker phase is controlled by a complex interplay between multiple afferent stimuli, and that serotonin plays a critical role in this process.