CGMP-DEPENDENT PROTEIN-KINASE INHIBITORS BLOCK LIGHT-INDUCED PHASE ADVANCES OF CIRCADIAN-RHYTHMS IN-VIVO

Synchronization of circadian rhythms is thought to be accomplished pri marily through daily phase delays and advances of the endogenous circa dian clock that, in mammals, is located in the hypothalamic suprachias matic nucleus (SCN). In the SCN, numerous second messenger pathways ma y participate in photic signal transduction, In these studies, the inv olvement of cyclic nucleotide-dependent kinases was examined in vivo u sing inhibitors of adenosine 3',5'-cyclic monophosphate (cAMP)-and gua nosine 3',5'-cyclic monophosphate (cGMP)-dependent kinase (PKA and PKG , respectively). In constant dark, selective and nonselective inhibito rs of PKG injected near the SCN of hamsters had no effect on phase del ays produced by light pulses given in the early subjective night (earl y in the animals' active period) but significantly attenuated phase ad vances induced late in the subjective night. PKA inhibition had no eff ect at either time point. In addition, cGMP agonists had no effect on rhythmicity in the absence of light. The activity is necessary, but no t sufficient, for normal photic responsiveness and that PKA activity i s not required. The phase dependence of the effect of PKG inhibition s upports the notion that photic entrainment is influenced by biochemica l pathways that differentially regulate sensitivity in a phase-depende nt manner.