Corticotropin-releasing hormone (CRH) is widely recognized as the primary mediator of the neuroendocrine and behavioral responses to stress, including stressinduced anxiety. The biological activity of CRH and other mammalian CRH-like peptides, such as urocortin, may be modulated by CRH-binding protein (CRH-BP). To assess directly the CRH-BP function, we created a mouse model of CRH-BP deficiency by gene targeting. Basal adrenocorticotropic hormone and corticosterone levels are unchanged in the CRH-BP-deficient mice, and the animals demonstrate a normal increase in adrenocorticotropic hormone and corticosterone after restraint stress. In contrast, adult male CRH-BP-deficient mice show significantly reduced body weight when compared with wild-type controls. CRH-BP-deficient mice also exhibit a significant increase in anxiogenic-like behavior as assessed by the elevated plus maze and defensive withdrawal tests. The increased anorectic and anxiogenic-like behavior most likely is caused by increased ''free'' CRH and͞or urocortin levels in the brain of CRH-BP-deficient animals, suggesting an important role for CRH-BP in maintaining appropriate levels of these peptides in the central nervous system.Corticotropin-releasing hormone (CRH) is the key mediator of the mammalian endocrine, behavioral, autonomic, and immune responses to stress (1). Within the hypothalamicpituitary-adrenal (HPA) axis, CRH is the principal regulator of pituitary adrenocorticotropic hormone (ACTH) and adrenal glucocorticoid secretion in response to stressful stimuli. Within the central nervous system (CNS), CRH acts as a neurotransmitter to elicit anxiogenic-like effects, decrease food intake, reduce weight gain, modulate locomotor activity, and improve arousal and learning (2-4). Aberrant CRH activity has been implicated in the pathophysiology of a variety of human psychiatric disorders, including major depression, anxiety disorders, and anorexia (1, 5).The actions of CRH in the CNS and pituitary are mediated via binding to two distinct CRH receptors, CRH-R1 and CRH-R2 (6). CRH also is bound by CRH-binding protein (CRH-BP), a 37-kDa protein that binds CRH with an affinity equal to or greater than the CRH-Rs (7-9). CRH-BP mRNA is expressed exclusively in the brain and pituitary of rodents, whereas it is detected in human brain, pituitary, liver, and placenta (9-11). Major CNS sites of CRH-BP mRNA expression in rodents are cerebral cortex, amygdala, bed nucleus of the stria terminalis, raphe nuclei, brainstem reticular formation, and olfactory, auditory, trigeminal and vestibular sensory relay systems (10). These sites of CRH-BP expression include several examples of cellular colocalization with CRHproducing neurons (i.e., lateral septal nucleus, bed nucleus of the stria terminalis, medial preoptic area, central nucleus of the amygdala) or CRH target cells, including anterior pituitary corticotropes that express CRH-R1 (10).Both CRH-BP and CRH-R2 mRNA are present in lateral septum, a site of expression of both CRH and urocortin (12). Uroco...