Melatonin and 5-hydroxytryptamine phase-advance the rat circadian clock by activation of nitric oxide synthesis

Melatonin and the 5-hydroxytryptamine (5-HT)1A/7 receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH DPAT) phase-advanced the circadian rhythm of neuronal action potential firing rate in rat suprachiasmatic nuclei (SCN) brain slices when applied at the end and middle of subjective day, respectively. The nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME), but not the less active enantiomer D-NAME, blocked the agonist-induced phase-advances. The effects of L-NAME were reversed by the NO precursor L-arginine. The NO donors 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP) mimicked the effects of melatonin and 8-OH DPAT at the appropriate times of day. This study demonstrates that the phase-shifting effects of melatonin and 5-HT on the SCN circadian pacemaker are mediated by NO.