Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress

Corticotropin-releasing hormone (Crh) is a critical coordinator of the hypo thalamic-pituitary-adrenal (HPA) axis. In response to stress, Crh released from the paraventricular nucleus (PVN) of the hypothalamus activates Crh re ceptors on anterior pituitary corticotropes, resulting in release of adreno corticotropic hormone (Acth) into the bloodstream. Acth in turn activates A cth receptors in the adrenal cortex to increase synthesis and release of gl ucocorticoids(1). The receptors for Crh, Crhr1 and Crhr2, are found through out the central nervous system and periphery. Crh has a higher affinity for Crhr1 than for Crhr2, and urocortin (Ucn); a Crh-related peptide, is thoug ht to be the endogenous ligand for Crhr2 because it binds with almost 40-fo ld higher affinity than does Crh (ref. 2). Crhr1 and Crhr2 share approximat ely 71% amino acid sequence similarity and are distinct in their localizati on within the brain and peripheral tissues(3-6). We generated mice deficien t for Crhr2 to determine the physiological role of this receptor. Crhr2-mut ant mice are hypersensitive to stress and display increased anxiety-like be haviour. Mutant mice have normal basal feeding and weight gain, but decreas ed food intake following food deprivation. intravenous Ucn produces no effe ct on mean arterial pressure in the mutant mice.