Growth hormone (GH)-releasing hormone (GHRH) is a hypothalamic neuro-endocrine which stimulates pituitary GH secretion. GHRH has become one of the best-documented sleep-promoting substances; much of this evidence was generated under the auspices of the previous grant. For example, administration of exogenous GHRH promotes sleep; inhibition of endogenous GHRH inhibits spontaneous sleep and blocks sleep rebound after sleep deprivation; hypothalamic GHRH mRNA varies in phase with the sleep-wake cycle. Despite this progress, the mechanisms by which GHRH promotes sleep, including the hypothalamic site of action, its somnogenic relationships to other members of the somatotropin system and sleep-linked changes in somatotropic gene expression are only partially understood.
The specific aims focus on these mechanistic issues.
In Specific Aim #1 GHRH and a GHRH antagonist will be micro-injected into the rat pre-optic region and sleep responses determined with the goal of mapping hypothalamic GHRH sleep-active sites.
In Specific Aim #2 the role of GHRH in alterations in sleep induced by somatostatinergic stimulation will be investigated. The effects of octreotide, a long-lasting somatostatin agonist, on sleep and, using micro-injection techniques, sleep-active hypothalamic-sensitive sites will be determined. The role of opiate receptors in somatostatin-altered sleep will be determined. Further, by pretreatment of rats with anti-GHRH sera before somatostatin treatment, the involvement of GHRH in somatostatin-induced sleep will be determined. Finally, sleep in a transgenic mouse over-expressing rat GH ectopically and the responsiveness of these mice to somatostatin will be assessed.
In Specific Aim #3 the diurnal variations and their locations in brain of GHRH mRNA, somatostatin mRNA and GHRH binding sites and changes in these substances over the course of sleep deprivation will be examined. Homogenate binding assays, in vitro receptor autoradiography and polymerase chain reaction techniques will be used on rat tissues. Anticipated results are expected to support the hypothesis that GHRH is a key regulatory component of sleep and provide explanation as to the mechanisms by which GHRH promotes sleep.
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