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Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress

Nature Genetics volume 24, pages 410414 (2000) | Download Citation

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Abstract

Corticotropin-releasing hormone (Crh) is a critical coordinator of the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, Crh released from the paraventricular nucleus (PVN) of the hypothalamus activates Crh receptors on anterior pituitary corticotropes, resulting in release of adrenocorticotropic hormone (Acth) into the bloodstream. Acth in turn activates Acth receptors in the adrenal cortex to increase synthesis and release of glucocorticoids1. The receptors for Crh, Crhr1 and Crhr2, are found throughout the central nervous system and periphery. Crh has a higher affinity for Crhr1 than for Crhr2, and urocortin (Ucn), a Crh-related peptide, is thought to be the endogenous ligand for Crhr2 because it binds with almost 40-fold higher affinity than does Crh (ref. 2). Crhr1 and Crhr2 share approximately 71% amino acid sequence similarity and are distinct in their localization within the brain and peripheral tissues3,4,5,6. We generated mice deficient for Crhr2 to determine the physiological role of this receptor. Crhr2-mutant mice are hypersensitive to stress and display increased anxiety-like behaviour. Mutant mice have normal basal feeding and weight gain, but decreased food intake following food deprivation. Intravenous Ucn produces no effect on mean arterial pressure in the mutant mice.

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Acknowledgements

We thank K. Creehan for animal assistance; G. Naeve for help with the image analysis; R. Picetti for help with behavioural analysis; S. Fitzpatrick for editorial assistance; and M. Stenzel-Poore and colleagues for sharing unpublished results. This work was supported in part by grants from the NIH (DK-26741), the Robert J. and Helen C. Kleberg Foundation, the Ludwick Family Foundation and The Foundation for Research. T.L.B. and G.W.S. were supported by NRSA fellowships DK09841 and DK09551, respectively. K.L.F. is a Pew Scholar.

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Affiliations

  1. Clayton Foundation Laboratories for Peptide Biology,

    • Tracy L. Bale
    • , George W. Smith
    • , Wylie W. Vale
    •  & Kuo-Fen Lee
  2. Laboratory of Neuronal Structure and Function, The Salk Institute, La Jolla, California, USA.

    • Raymond Chan
    •  & Paul E. Sawchenko
  3. Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California, USA.

    • Angelo Contarino
    • , Lisa H. Gold
    •  & George F. Koob

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Correspondence to Kuo-Fen Lee.

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DOI

https://doi.org/10.1038/74263

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