IL-1 is a mediator of increases in slow-wave sleep induced by CRH receptorblockade

We hypothesize that corticotropin-releasing hormone (CRH), a regulator of t he hypothalamic-pituitary-adrenal (HPA) axis, is involved in sleep-wake reg ulation on the basis of observations that the CRH receptor antagonist astre ssin, after a delay of several hours, reduces waking and increases slow-wav e sleep (SWS) in rats. This delay suggests a cascade of events that begins with the HPA axis and culminates with actions on sleep regulatory systems i n the central nervous system. One candidate mediator in the brain for these actions is interleukin (IL)-1. IL-1 promotes sleep, and glucocorticoids in hibit IL-1 synthesis. In this study, central administration of 12.5 mu g as tressin into rats before dark onset reduced corticosterone 4 h after inject ion and increased mRNA expression for IL-1 alpha and IL-1 beta but not for IL-6 or tumor necrosis factor-alpha in the brain 6 h after injection. To de termine directly whether IL-1 is involved in astressin-induced alterations in sleep-wake behavior, we then pretreated rats with 20 mu g anti-IL-1 beta antibodies before injecting astressin. The increase in SWS and the reducti on in waking that occur after astressin are abolished when animals are pret reated with anti-IL-1 beta. These data indicate that IL-1 is a mediator of astressin-induced alterations in sleep-wake behavior.