Mechanisms of growth hormone-releasing hormone-mediated humoral regulation of sleep

This work was undertaken to gain an understanding of the mechanisms involved in growth hormone (GH)-releasing hormone (GHRH)-mediated humoral regulation of sleep. GHRH is a hypothalamic neurocrine which stimulates pituitary GH release. GHRH is one of the best documented sleep-promoting substances involved in the humoral regulation of sleep and forms part of the homeostatic sleep process. The first hypothesis I tested was that a chronic deficiency in GHRH and/or GH induces sleep alterations. It was tested in transgenic mice in which exogenous human GH was expressed in catecholaminergic neurons in the central nervous system including hypothalamic nuclei. Sleep-wake activity of transgenic mice bearing the human GH gene was compared with their normal littermates. I found that non-rapid eye movement sleep (NREMS) is suppressed in this transgenic mouse model with a deficiency in the somatotropic axis. The results suggest the somatotropic axis has a tonic contribution in the maintenance of sleep.;The last hypothesis I tested was that GHRH mediates sleep-wake activity via somnogenic structures residing in the preoptic area of the basal forebrain. Rat GHRH, or its competitive antagonist, was microinjected intrapreoptically at dark onset or light onset, respectively. The GHRH antagonist was also microinjected at the termination of a 3-h sleep deprivation. I demonstrated that sleep increased or decreased after microinjection of GHRH or its antagonist, respectively. GHRH antagonist also attenuated sleep rebound after sleep deprivation. These experiments provide direct evidence that sleep-promoting activity of GHRH is mediated by the somnogenic structures in the preoptic area of the basal forebrain.;The next hypothesis I tested was that hypothalamic GHRH responds to alterations in sleep-wake activity. Hypothalamic GHRH mRNA levels and peptide contents were examined in rats after sleep deprivation and compared with time-matched non-sleep deprived controls. Hypothalamic GHRH mRNA levels increased after sleep deprivation whereas hypothalamic GHRH peptide contents decreased after sleep deprivation. Sleep deprivation also induced decreases in hypothalamic somatostatin (SRIH) mRNA levels. These findings support the role of GHRH in humoral regulation of sleep and suggest the existence of a reciprocal interaction between GHRHergic and somatostatinergic activities in the modulation of sleep-wake activity.