Characterization of melatonin-induced fos-like immunoreactivity in the hypothalamic suprachiasmatic nucleus of the rat

The hypothalamic suprachiasmatic nucleus (SCN) is primarily responsible for the regulation of circadian rhythmicity. Melatonin, the pineal-derived neurohormone, modulates the rhythmic output of the SCN. Properly timed exposure to melatonin is able to induce changes in rhythmic function and thereby entrain circadian rhythms of activity. c-fos is an immediate early gene that is transiently expressed in neurons in response to receptor activation. The ventrolateral portion of the SCN (vSCN) is activated in response to phase-shifting stimuli, an event which is marked by an increase in the expression of c-fos. In the present study, rats systemically administered the melatonin agonist 2-iodomelatonin at CT 22 demonstrated significant dose-dependent Fos immunoreactivity within the vSCN, an effect which was significantly inhibited by the melatonin antagonist N-acetyltryptamine. The Fos expression observed in the vSCN was not affected by treatment with the serotonin antagonist ketanserin or the alpha-adrenergic antagonist phentolamine. Moreover, antisense oligonucleotides to c-fos, significantly blocked the ability of 2-iodomelatonin to induce Fos expression in the vSCN at CT 22. These results pharmacologically characterize melatonin-induced c-fos expression in the rat vSCN and provide evidence to support a c-fos-mediated mechanism through which the activation of melatonin receptors may be linked to the long-term molecular regulation of circadian rhythms controlled by the SCN.