Translational and Transcriptional Inhibitors Block Serotonergic Phase Advances of the Suprachiasmatic Nucleus Circadian Pacemaker In Vitro

The mammalian circadian pacemaker is located in the suprachiasmatic nucleus (SCN). Various inputs modulate pacemaker phase, including the serotonergic (5HTergic) input from the midbrain raphe. 5HT phase-advances the SCN pacemaker when applied during mid subjective day. In vitro studies indicate that 5HT advances the mammalian circadian pacemaker through a process that includes stimulating 5HT₇ receptors, activating protein kinase A, and opening K⁺ channels. How these cytoplasmic and membrane events translate into a shift in the molecular core of the circadian oscillator is not known. To further understand this process, the authors investigated whether 5HTergic phase advances require transcription or translation. Using two reversible translational inhibitors, anisomycin and cycloheximide, the authors show that inhibiting protein synthesis blocks 5HTergic phase shifts. The authors further show that the transcriptional inhibitor 5,6-dichloro-1-[.beta]-ribobenzimidazole also blocks 5HTergic phase shifts. These results are similar to those found previously with respect to 5HTergic modulation of the Aplysia ocular circadian clock, and suggest that 5HT may phase-shift the SCN pacemaker through increasing transcription and translation of specific proteins.