Serotonergic potentiation of dark pulse-induced phase-shifting effects at midday in hamsters

In mammals, resetting of the suprachiasmatic clock (SCN) by behavioral activation or serotonin (5-HT) agonists is mimicked by dark pulses, presented during subjective day in constant light (LL). Because behavioral resetting may be mediated in part by 5-HT inputs to the SCN, here we determined whether 5-HT system can modulate dark-induced phase-shifts in Syrian hamsters housed in LL. Two hours of darkness at mid-subjective day (circadian time 6; CT-6) resulted in increased concentrations of 5-HT in the SCN tissue and induction of c-FOS expression in the raphe nuclei. Injections of the 5-HT(1A/7) agonist +8-OH-DPAT or dark pulses at CT-6 induced phase-advances of the wheel-running activity rhythm and down-regulated the expression of the clock genes Per1-2 and c-FOS in the SCN in a similar way. The combination of both treatments [+8-OH-DPAT + dark pulses], however, resulted in larger phase-advances, while associated molecular changes were not significantly modified, except for the gene Dbp, in comparison to +8-OH-DPAT or dark pulses alone. Dark resetting was blocked by pre-treatment with a 5-HT(7) antagonist, but not with a 5-HT(1A) antagonist. The additive phase-shifts of two different cues to reset the SCN clock open wide the gateway for non-photic shifting, leading to new strategies in chronotherapy.