Deletion of Crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2

Corticotropin-releasing hormone(1,2) (Crh), a 41-residue polypeptide, activ ates two G-protein-coupled receptors, Crhr1 (refs 3-5) and Crhr2 (refs 6-9) , causing (among other transductional events) phosphorylation of the transc ription factor Creb (ref. 10). The physiologic;role of these receptors is o nly partially understood. Here we report that male, but not female, Crhr2-d eficient mice exhibit enhanced anxious behaviour in several tests of anxiet y in contrast to mice lacking Crhr1 (refs 11,12). The enhanced anxiety of C rhr2-deficient mice is not due to changes in hypothalamic-pituitary-adrenal (HPA) axis activity, but rather reflects impaired responses in specific br ain regions involved in emotional and autonomic function, as monitored by a reduction of Creb phosphorylation in male, but not female, Crhr2(-/-) mice . We propose that Crhr2 predominantly mediates a central anxiolytic respons e, opposing the general anxiogenic effect of Crh mediated by Crhr1. Neither male nor female Crhr2-deficient mice show alterations of baseline feeding behaviour. Both respond with increased edema formation in response to therm al exposure, however, indicating that in contrast to its central role in an xiety, the peripheral role of Crhr2 in vascular permeability is independent of gender.