Sleep in mice with nonfunctional growth hormone-releasing hormone receptors

Abstract

The role of the somatotropic axis in sleep regulation was studied by using the lit/lit mouse with nonfunctional growth hormone (GH)-releasing hormone (GHRH) receptors (GHRH-Rs) and control heterozygous C57BL/6J mice, which have a normal phenotype. During the light period, the lit/lit mice displayed significantly less spontaneous rapid eye movement sleep (REMS) and non-REMS (NREMS) than the controls. Intraperitoneal injection of GHRH (50 microg/kg) failed to promote sleep in the lit/lit mice, whereas it enhanced NREMS in the heterozygous mice. Subcutaneous infusion of GH replacement stimulated weight gain, increased the concentration of plasma insulin-like growth factor-1 (IGF-1), and normalized REMS, but failed to restore normal NREMS in the lit/lit mice. The NREMS response to a 4-h sleep deprivation was attenuated in the lit/lit mice. In control mice, intraperitoneal injection of ghrelin (400 microg/kg) elicited GH secretion and promoted NREMS, and intraperitoneal administration of the somatostatin analog octretotide (Oct, 200 microg/kg) inhibited sleep. In contrast, these responses were missing in the lit/lit mice. The results suggest that GH promotes REMS whereas GHRH stimulates NREMS via central GHRH-Rs and that GHRH is involved in the mediation of the sleep effects of ghrelin and somatostatin.

The Somatostatin Analogue Octreotide Impairs Sleep and Decreases EEG Sigma Power in Young Male Subjects

“…Our finding in humans is at variance with the increase of SWA, which followed the suppression of NREMS after octreotide in the rat (Beranek et al, 1997(Beranek et al, , 1999. The decrease of stage 4 sleep after octreotide is in contrast to the increase of SWS after GHRH in humans (Kerkhofs et al, 1993;Marshall et al, 1996;Steiger et al, 1992) and of NREMS in laboratory animals (Obál et al, 1988Ehlers et al, 1986;Nistico et al, 1987;Zhang et al, 1999) and after ghrelin in humans (Weikel et al, 2003) and in mice (Obál et al, 2003). We showed previously that the timing of GHRH administration is a crucial issue.…”

“…These sites correspond to the location of the GHRHergic cell bodies and terminals . The sleep response to octreotide was attenuated in transgenic mice with decreased GHRH production (Hajdu et al, 2002) and was abolished in mice with deficient GHRH receptors (Obál et al, 2003).…”

“…Recently, ghrelin was identified as another endogenous GH secretagogue (Kojima et al, 1999). Interestingly, ghrelin shares the sleep-promoting effect of GHRH in humans (Weikel et al, 2003) and mice (Obál et al, 2003). The endogenous antagonist of GHRH in the pituitary release of GH is somatostatin (SRIF).…”

“…GHRH was found, whereas it was weaker than that in young men . In various animal models of reduced GHRH activity NREMS is decreased, as after the suppression of endogenous GHRH by GHRH antibodies (Obál et al, 1991), GHRH antagonists (Obál et al, 1992), in mutant dwarf rats , in dwarf mice with GHRH receptor deficiencies (Obál et al, 2003), and in transgenic mice with decreased GHRH production (Zhang et al, 1996). The diurnal variation of GHRH mRNA levels (Bredow et al, 1996) and GHRH contents in the rat hypothalamus suggests distinct synthesis and release of GHRH, when the peak of NREMS occurs during the first portion of the rest period.…”

Ghrelin Stimulates Appetite, Imagination of Food, GH, ACTH, and Cortisol, but does not Affect Leptin in Normal Controls

“…Ghrelin enhanced eating both in mice with intact and deficient GHRH receptors. On the contrary, promotion of sleep required intact GHRH receptors (Obál et al, 2003).…”