Urocortin 1 (UCN 1) is a corticotropin-releasing factor (CRF)-like peptide whose role in stress is not well characterized. To study the physiological role of UCN 1 in the response of the hypothalamic pituitary adrenal (HPA) axis to stress we generated UCN 1 knock-out (KO) mice and examined their adaptation to repeated restraint and to cold environment. Wild type (WT) and UCN 1 KO animals were restrained hourly for 15 min from 9 am to 2 pm and blood samples were obtained for corticosterone measurement. WT animals adapted to repeated restraint with a decreased corticosterone response: the restraint-stimulated corticosterone levels fell from 215±31 ng/ml in naive animals to 142±50 ng/ml in mice subjected to repeated restraint (P<0.01); and from 552±98 ng/ml to 314±58 ng/ml (P<0.001), in males and females respectively. Male UCN 1 KO mice did not show any adaptation to repeated restraint; instead, it increased restraint-stimulated corticosterone levels from 274±80 ng/ml in naive animals to 480±75 ng/ml in mice subjected to repeated restraint (P<0.001). Female UCN 1 KO mice showed only a partial adaptation to repeated restraint with a decrease in the restraint-stimulated corticosterone response from 631±102 ng/ml in naive animals to 467±78 ng/ml in mice subjected to repeated restraint (P<0.01). In addition, UCN 1 KO mice showed no corticosterone response to 2 h cold environment. These data demonstrate an important role for UCN 1 in the HPA axis adaptation to repeated restraint and in the corticosterone response to a cold environment.