STUDY OBJECTIVES: Corticotropin-releasing hormone (CRH) is the major activator of the hypothalamic-pituitary-adrenocortical (HPA) system and orchestrates the neuroendocrine, autonomous as well as behavioral responses to stress. Many studies suggest an influence of CRH on sleep-wake regulation even in the absence of stressors. However, none of these studies yet clearly distinguished between central and peripheral effects of CRH. Therefore, we investigated in CNS-specific CRH receptor type 1 deficient mice whether centrally administered CRH could induce its sleep-wake modulatory effects without peripheral induction of HPA activity. DESIGN: Male mice (C57BL/6J, CNS-specific CRH-R1 knockout [CKO] mice and their control littermates [CL]) were intracerebroventricularily (i.c.v.) injected with vehicle or 3 different doses of CRH shortly before the beginning of the light period. Electroencephalogram (EEG) and electromyogram (EMG) were monitored to compare the effects of CRH on vigilance states with or without presence of central CRH-R1. To quantify HPA-axis reactivity to CRH injections in CKO and CL animals, blood samples were analyzed to determine plasma corticosterone concentrations. RESULTS: I.c.v. injections of CRH promoted wakefulness while decreasing NREMS in C57BL/6J and CRH-R1 CL animals, whereas such changes were not exerted in CKO mice. However, REMS suppression after CRH application persisted in all animals. I.c.v. injected CRH increased plasma corticosterone levels in both CL and CKO mice. CONCLUSIONS: The results demonstrated that CRH has a major impact on wake and NREMS regulation which is predominantly mediated through central CRH-R1. Peripheral actions of CRH, i.e., elevated HPA activity, may interfere with its central effects on REMS but not on NREMS suppression.