We hypothesize that corticotropin-releasing hormone (CRH), a regulator of the hypothalamic-pituitary-adrenal (HPA) axis, is involved in sleep-wake regulation on the basis of observations that the CRH receptor antagonist astressin, after a delay of several hours, reduces waking and increases slow-wave 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 in the central nervous system. One candidate mediator in the brain for these actions is interleukin (IL)-1. IL-1 promotes sleep, and glucocorticoids inhibit IL-1 synthesis. In this study, central administration of 12.5 µg astressin into rats before dark onset reduced corticosterone 4 h after injection and increased mRNA expression for IL-1 and IL-1 but not for IL-6 or tumor necrosis factor- in the brain 6 h after injection. To determine directly whether IL-1 is involved in astressin-induced alterations in sleep-wake behavior, we then pretreated rats with 20 µg anti-IL-1 antibodies before injecting astressin. The increase in SWS and the reduction in waking that occur after astressin are abolished when animals are pretreated with anti-IL-1. These data indicate that IL-1 is a mediator of astressin-induced alterations in sleep-wake behavior.