Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2

Nat Genet. 2000 Apr;24(4):415-9. doi: 10.1038/74271.


Corticotropin-releasing hormone (Crh), a 41-residue polypeptide, activates two G-protein-coupled receptors, Crhr1 and Crhr2, causing (among other transductional events) phosphorylation of the transcription factor Creb. The physiologic role of these receptors is only partially understood. Here we report that male, but not female, Crhr2-deficient mice exhibit enhanced anxious behaviour in several tests of anxiety in contrast to mice lacking Crhr1. The enhanced anxiety of Crhr2-deficient mice is not due to changes in hypothalamic-pituitary-adrenal (HPA) axis activity, but rather reflects impaired responses in specific brain 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 response, 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 thermal exposure, however, indicating that in contrast to its central role in anxiety, the peripheral role of Crhr2 in vascular permeability is independent of gender.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Animals
  • Anxiety / genetics*
  • Anxiety Disorders / genetics
  • Brain / metabolism
  • Corticosterone / blood
  • Corticotropin-Releasing Hormone / administration & dosage
  • Corticotropin-Releasing Hormone / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Edema / genetics
  • Feeding Behavior / physiology
  • Female
  • Gene Deletion*
  • Hot Temperature / adverse effects
  • Hypothalamo-Hypophyseal System / physiology
  • Injections, Intraventricular
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Phosphorylation
  • Pituitary-Adrenal System / physiology
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Receptors, Corticotropin-Releasing Hormone / genetics*
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Restraint, Physical
  • Sex Factors
  • Stress, Physiological / blood
  • Stress, Physiological / metabolism
  • Stress, Physiological / physiopathology
  • Weight Gain


  • CRF receptor type 2
  • Cyclic AMP Response Element-Binding Protein
  • Proto-Oncogene Proteins c-fos
  • Receptors, Corticotropin-Releasing Hormone
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Corticosterone