Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response, causing stimulation of corticotropin and glucocorticoid secretion. CRH is also widely believed to mediate stress-induced behaviors, implying a broader, integrative role for the hormone in the psychological stress response. Mice lacking the CRH gene exhibit normal stress-induced behavior that is specifically blocked by a CRH type 1 receptor antagonist. The other known mammalian ligand for CRH receptors is urocortin. Normal and CRHdeficient mice have an identical distribution of urocortin mRNA, which is confined to the region of the Edinger-Westphal nucleus, and is absent from regions known to mediate stress-related behaviors. Since the Edinger-Westphal nucleus is not known to project to any brain regions believed to play a role in anxiety-like behavior, an entirely different pathway must be postulated for urocortin in the Edinger-Westphal nucleus to mediate these behaviors in CRH-deficient mice. Alternatively, an unidentified CRH-like molecule other than CRH or urocortin, acting through the CRH receptors in brain regions believed to mediate stressinduced behaviors, may mediate the behavioral response to stress, either alone or in concert with CRH.Stress, defined as the response of the body to any threatening demand (1), can be broadly separated into physiological responses, including the stimulation of adrenal glucocorticoid secretion, and behavioral responses, including anxiety and fearful behavior. Alterations in the stress-response system are believed to underlie many anxiety-related disorders (2-5). Corticotropinreleasing hormone (CRH) has been implicated in both physiological and behavioral stress responses. CRH was identified by its ability to stimulate adrenocorticotropic hormone (ACTH) secretion from anterior pituitary corticotrophs, thus activating the hypothalamic-pituitary-adrenal (HPA) axis (6). In addition, infusion of CRH into the brain was found to cause stress-like behaviors (7), suggesting that CRH integrates physiological and behavioral activities into a generalized stress response. Subsequently, many other pharmacological studies have implicated CRH in the behavioral response to stressors. These studies confirmed that intracerebral infusion of CRH induces stress-like behaviors and additionally that intracerebral infusions of CRH antagonists blunt the behavioral response to a stressor (8-10). Furthermore, transgenic mice that overexpress CRH exhibit increased anxiety-like behavior (11).The role of the CRH receptor in the behavioral stress response has been further evaluated. The two known CRH receptors, type 1 and type 2 (12), both consist of a 7-transmembrane helix functionally coupled to adenylate cyclase via G s . For the most part, the anatomical distributions of the two CRH receptors are distinct, with the type 1 receptor expressed in the central nervous system in regions including neo-, olfactory, and hippocampal cortices, subcortical limbic structures in the septal region and amygdala, ce...