Effects of nitric oxide synthase inhibitors on N-methyl-d-aspartate-induced phase delay of circadian rhythm of neuronal activity in the rat suprachiasmatic nucleus in vitro

Excitatory amino acid (EAA) receptors such as N-methyl-d-aspartate (NMDA) and non-NMDA receptors have been suggested to play an important role in the regulation of photic information from the retina to the suprachiasmatic nucleus (SCN). Therefore, we investigated the role of glutamate as a retinohypothalamic transmitter by analyzing the phase-resetting effects of NMDA and a non-NMDA agonist, (R,S)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), on the circadian rhythm of SCN firing activity. Nitric oxide (NO) production is believed to be an essential intermediate in NMDA-induced cGMP production in the CNS. Thus, we examined the effects of blockers of NO production on NMDA- or AMPA-induced phase delay of SCN activity rhythm. N-nitro-l-arginine methylester (l-NAME) blocked NMDA- but not AMPA-induced phase shift, indicating the involvement of NO synthesis in NMDA-induced phase changes. l-arginine but not d-arginine caused a phase delay, and l-NAME blocked l-arginine-induced phase delay. In addition, cotreatment with NMDA and l-arginine did not have an additive effect. These results suggest that NO production itself is involved in the phase change of SCN neuron activity, and NMDA-induced phase changes are also mediated via activation of NO synthesis in this nucleus.