Early studies have reported a phase-shifting effect of growth hormone secretagogues (GHSs). This study aimed to determine the mechanism of action of GHSs. We examined the response of the hypothalamic suprachiasmatic nuclei (SCN) to growth hormone releasing peptide-6 (GHRP-6) by assessing effects on the phase of locomotor activity rhythms, SCN neuronal discharges, and the potential signaling pathways involved in the drug action on circadian rhythms. The results showed that bolus administration of GHRP-6 (100 μg/kg, i.p.) at the beginning of subjective night (CT12) induced a phase delay of the free running rhythms in male C57BL/6J mice under constant darkness (DD), but did not elicit phase shift at other checked circadian time (CT) points. The phase-delay effect of GHRP-6 was abolished by D-(+)-Lys-GHRP-6 (GHS receptor antagonist), KN-93 (CaMKII inhibitor) or anti-p-CREB antibody, respectively. Further analyses demonstrated that GHRP-6 at CT12 induced higher calcium mobilization and neuronal discharge in the SCN compared with that at CT6, decreased the levels of glutamate and GABA, increased the levels of p-CaMKII, p-CREB and Per1, and delayed the circadian expressions of Clock, Bmal1 and PK2 in the SCN, these signaling changes resulted in behavioral phase delay. Collectively, GHRP-6 induces a circadian time-dependent phase delay via activating GHS receptor and the downstream signaling, which is partially similar to the signaling cascade of light-induced phase delay at early night. These novel observations may help to better understand the role of GHSs in circadian physiology.
- growth substances
- phase shift
- nonphotic cues
- Copyright © 2014, American Journal of Physiology - Endocrinology and Metabolism