Rat strains that differ in corticotropin-releasing hormone production exhibit different sleep-wake responses to interleukin 1.
Corticotropin-releasing hormone (CRH) is a mediator of responses to a variety of stressors, including immune challenge. CRH and the hypothalamic-pituitary-adrenal (HPA) axis constitute a negative feedback mechanism for actions of immunomodulators, such as interleukin (IL) 1. CRH is a potent inducer of waking, whereas IL-1 induces slow-wave sleep (SWS). We hypothesize that the complex changes in sleep-wake behavior during immune challenge are mediated in part by CRH and its antagonism of IL-1-induced enhancement of SWS. To further explore this hypothesis, we administered IL-1beta intracerebroventricularly into rats of genetically related strains that differ in CRH/HPA axis responsiveness to IL-1 and determined subsequent alterations in their sleep-wake behavior. Sprague-Dawley rats responded to central administration of IL-1 with alterations in sleep-wake behavior as previously reported; SWS increased, and rapid eye movement sleep (REMS) and waking decreased. CRH and the HPA axis of Lewis rats are reported to be hyporesponsive to challenge; the onset of the IL-1-induced increase in SWS was quicker and the peak magnitude of the response greater than in Sprague-Dawley rats. In contrast, Fischer 344 rats exhibit greater CRH release and HPA axis activation in response to IL-1. IL-1 induced a profound and transient increase in waking of Fischer 344 rats before SWS increased. The febrile responses to IL-1 of Fischer 344 and Lewis rats were identical and of greater magnitude than those observed in Sprague-Dawley rats. Pretreatment with the CRH receptor antagonist alpha-helical CRH(9-41) blocked the initial IL-1-induced increase in waking of Fischer 344 rats. CRH receptor blockade did not affect the IL-1-induced alterations in sleep-wake behavior of Lewis or Sprague-Dawley rats or brain temperature of any rat strain. These observations support the hypothesis that CRH is both a modulator of responses to IL-1 and is involved in the regulation of waking.
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Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, Tex., USA. mopp@umich.edu
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D000818:Animals; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D012890:Sleep / Q000187:drug effects*; D013045:Species Specificity; D014851:Wakefulness / Q000187:drug effects*
D006727:Hormone Antagonists; D007375:Interleukin-1; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone; C045089:corticotropin releasing hormone (9-41); D003345:Corticosterone