Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2

The actions of corticotropin-releasing hormone (Crh), a mediator of endocri ne(1) and behavioural responses to stress(2), and the related hormone uroco rtin(3) (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2 (refs 4,5). These receptors may exhibit distinct functions due to un ique tissue distribution(6) and pharmacology(4,5). Crhr-null mice have defi ned central functions for Crhr1 in anxiety and neuroendocrine stress respon ses(7,8). Here we generate Crhr2(-/-) mice and show that Crhr2 supplies reg ulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress re sponse. Although initiation of the stress response appears to be normal. Cr hr2(-/-) mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticost erone levels remain elevated 90 minutes after stress in Crhr2(-/-) mice. In addition, stress-coping behaviours associated with dearousal are reduced i n Crhr2(-/-) mice. We also demonstrate that Crhr2 is essential for sustaine d feeding suppression (hypophagia) induced by Ucn. Feeding is initially sup pressed in Crhr2(-/-) mice following Ucn, but Crhr2(-/-) mice recover more rapidly and completely than do wild-type mice. In addition to central nervo us system effects, we found that, in contrast to wild-type mice, Crhr2(-/-) mice fail to show the enhanced cardiac performance or reduced blood pressu re associated with systemic Ucn, suggesting that Crhr2 mediates these perip heral haemodynamic effects. Moreover, Crhr2(-/-) mice have elevated basal b lood pressure, demonstrating that Crhr2(-/-) participates in cardiovascular homeostasis. Our results identify specific responses in the brain and peri phery that involve Crhr2.