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

Abstract

The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- 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 corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.

Mice Deficient for Both Corticotropin-Releasing Factor Receptor 1 (CRFR1) and CRFR2 Have an Impaired Stress Response and Display Sexually Dichotomous Anxiety-Like Behavior

“…Ucn mRNA in the Edinger-Westphal (EW) nucleus is also increased in the CRFR2-mutant mice. The reported phenotype for these mice contains some discrepancies, because one group found a trend in anxiety levels in the mutant mice that did not reach significance (Coste et al, 2000), whereas another group only detected anxiety-like behavior in male but not female mutant mice (Kishimoto et al, 2000). Differences in breeding schemes and mouse strains have been proposed to explain the variation in results obtained for these mice.…”

“…In direct opposition to the CRFR1-mutant mice, CRFR2-mutant mice display increased anxiety-like behavior and are hypersensitive to stress (Bale et al, 2000;Coste et al, 2000). These mice respond not only more rapidly to stress but also with greater amplitude, with mutant mouse corticosterone levels doubling control levels after 10 min of restraint (Bale et al, 2000).…”

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

“…In contrast, opiate-withdrawn CRF 2 receptordeficient mice display unaltered CRF 1 receptor-dependent neuroendocrine and behavioral responses (Ingallinesi et al, 2012;Papaleo et al, 2008), suggesting that resilience to the stress-induced reemergence of motivational alterations is specifically because of the lack of functional CRF 2 receptors. The CRF 2 receptor has been largely implicated in the stress response (Bale et al, 2000;Coste et al, 2000;Kishimoto et al, 2000). However, herein drug-naive mice of either genotype do not differ following exposure to the FWS or the EPS.…”

Measuring normal and pathological anxiety-like behaviour in mice: a review

“…For example, it was demonstrated that CRF transgenic mouse lines overexpressing CRF exhibited a behavioral state resembling that produced by anxiety in the elevated plus-maze and the light/dark tests [82]. Moreover, three recent studies reported that male, but not female, CRF 2 receptor-deficient mice exhibit enhanced anxious behavior in several tests of anxiety, including the elevated plus-maze, the light/dark and the open-field tests [3,22,48]. Finally, CRF-binding protein-deficient mice were shown to exhibit a significant increase in a fear-related behavior in the elevated plus-maze, open-field and defensive withdrawal tests [46,71].…”