The role of corticotropin-releasing factor receptors in stress and anxiety.

Corticotropin releasing factor (CRF) is a critical integrator of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. CRF and its related molecule urocortin (UCN) bind CRF receptor 1 (CRFR1) and CRFR2 with distinct affinities. Mice deficient for CRFR1 or CRFR2 were generated in order to determine the physiological role of these receptors. While CRFR1-mutant mice show a depleted stress response and display anxiolytic-like behavior, CRFR2-mutant mice are hypersensitive to stress and display anxiogenic-like behavior. Both CRFR1- and CRFR2-mutant mice show normal basal feeding and weight gain, but CRFR2-mutant mice exhibit decreased food intake following a stress of food deprivation. While CRFR2-mutant mice display increased levels of CRF mRNA in the central nucleus of the amygdala (cAmyg) but not in the paraventricular nucleus of the hypothalamus (PVN), the CRFR1-mutant mice express high levels of CRF in the PVN but normal levels in the cAmyg. CRFR2-mutant mice also display increased levels of Ucn mRNA and protein in the edinger westphal nucleus (EW) as well as an increased number of cells expressing Ucn. The levels of these CRF-receptor ligands reflect the state of the receptor-deficient mice. These results demonstrate a possible modulatory function of CRFR2 in response to CRFR1 stimulation of the HPA axis or anxiety.