SLEEP REGULATION--INVOLVEMENT OF GRF-LIKE PEPTIDES

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The broad objective of this proposal is to examine the hypothesis that hypothalamic GRF-like peptides are involved in sleep regulation, i.e., GRF (growth hormone releasing factor), VlP (vasoactive intestinal peptide) and PHI (peptide histidine- isoleucine). We hypothesize that GRF stimulation of GH (growth hormone) secretion and promotion of nonREM sleep (NREMS) are parallel, albeit dissociable, functions of hypothalamic neurons which project to both the median eminence and basal forebrain hypnogenic areas. Further, GH and SOM (somatostatin) released by GRF may promote REMS (REM sleep) subsequent to NREMS. VlP and PHI are structurally related to GRF and stimulate secretion of pituitary PRL (prolactin) that can reach the brain by means of a specific transport mechanism. The VIP/PHI-PRL axis is assumed to have a permissive or facilitatory effect on REMS. Some previously proposed sleep factors, e.g., interleukin-l (ILl), may act through these endocrine mechanisms. The hypothesis is based upon preliminary data and previous reports: 1) GH and PRL secretions are coupled to sleep; 2) GRF promotes first NREMS then REMS, while GH and SOM selectively promote REMS; 3) both VIP and PRL increase REMS; and 4) proposed sleep factors affect endocrine regulation. The hypothesis will be tested by studying the effects of GRF, VIP, PHI, and PRL on sleep, thermoregulation and secretion of hormones after intracerebroventricular, intracerebral, systemic injection. Antibodies against GRF and pharmacological lesions of GRF neurons will be used to block endogenous GRF actions to determine the role of endogenous GRF in physiological sleep and in sleep (and GH secretion) elicited by ILl. The contribution of endogenous PRL to physiological sleep and to REMS elicited by VIP and PHI will be studied in animals pretreated with PRL antibodies. Sleep-related variations in GRF secretions will be measured. The experiments will be carried out in rats and rabbits chronically implanted with EEG electrodes, intracerebral cannulas and intracardial catheters. Hormone levels will be measured by means of ELISA or RIA from serial samples. We anticipate that the results will provide evidence that endocrine and sleep regulations involve common regulatory pathways.