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Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1

Nature Genetics volume 19, pages 162–166 (1998)Cite this article

Abstract

Corticotropin-releasing hormone (CRH) is a potent mediator of endocrine, autonomic, behavioural and immune responses to stress, and has been implicated in the stress-like and other aversive consequences of drug abuse, such as withdrawal from alcohol1,2. Two CRH receptors, Crhr1 and Crhr2, have been identified in the mouse3,4. Crhr1 is highly expressed in the anterior pituitary, neocortex, hippocampus, amygdala and cerebellum, and activation of this receptor stimulates adenylate cyclase5,6. Here we show that in mice lacking Crhr1, the medulla of the adrenal gland is atrophied and stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone is reduced. The homozygous mutants exhibit increased exploratory activity and reduced anxiety-related behaviour under both basal conditions and following alcohol withdrawal. Our results demonstrate a key role of the Crhr1 receptor in mediating the stress response and anxiety-related behaviour.

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Figure 1: Targeted mutation of Crhr1 in mouse ES cells.
Figure 2: Plasma ACTH and corticosterone levels.
Figure 3: Histological and immunohistochemical analysis.
Figure 4: Locomotor activity under basal conditions and following alcohol withdrawal in the open field.
Figure 5: Anxiety-related behaviour under basal and alcohol-withdrawal conditions in the light-dark box.

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References

  1. Menzaghi, F. et al. The role of corticotropin-releasing factor in the anxiogenic effects of ethanol withdrawal. Ann. N. Y. Acad. Sci. 739, 176 –184 (1994).

    Article  CAS  Google Scholar 

  2. Pich, E.M. et al. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J. Neurosci. 15, 5439–5447 (1995).

    Article  CAS  Google Scholar 

  3. Vita, N. et al. Primary structure and functional expression of mouse pituitary and human brain corticotrophin releasing factor receptors. FEBS Lett. 335, 1–5 (1993).

    Article  CAS  Google Scholar 

  4. Kishimoto, T Pearse, R.V. Lin C.R. Rosenfeld, M.G. A sauvagine/corticotropin-releasing factor receptor expressed in heart and skeletal muscle. Proc. Natl. Acad. Sci. USA 92, 1108–1112 (1995

    Article  CAS  Google Scholar 

  5. Chalmers, D.T. Lovenberg, T.W. De Souza, E.B. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J. Neurosci. 15, 6340–6350 (1995).

    Article  CAS  Google Scholar 

  6. De Souza, E.B. Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinol. 20, 789–819 (1995).

    Article  CAS  Google Scholar 

  7. Aguilera, G. Abou-Samra, A.B. Harwood, J.P. Catt, K.J. Corticotropin releasing factor receptors: characterization and actions in the anterior pituitary gland. Adv. Exp. Med. Biol. 245, 83–106 (1988).

    Article  CAS  Google Scholar 

  8. Bilezikjian L.M. Vale, W.W. Glucocorticoids inhibit corticotropin-releasing factor-induced production of adenosine 3´,5´-monophosphate in cultured anterior pituitary cells. Endocrinol. 113, 657–662 (1983).

    Article  CAS  Google Scholar 

  9. Vale,W. Spiess, J. Rivier, C. Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213, 1394–1397 (1981).

    Article  CAS  Google Scholar 

  10. Holsboer, F. Spengler, D. Heuser, I. The role of corticotropin-releasing hormone in the pathogenesis of Cushing's disease, anorexia nervosa, alcoholism, affective disorders and dementia. Prog. Brain Res. 93, 385–416 (1992).

    Article  CAS  Google Scholar 

  11. Owens, M.J. Nemeroff, C.B. Physiology and pharmacology of corticotropin-releasing factor. Pharmacol. Rev. 43, 425–473 (1991).

    CAS  PubMed  Google Scholar 

  12. Swanson, L.W. Simmons, D.M. Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat. J. Comp. Neurol. 285, 413–435 ( 1989).

    Article  CAS  Google Scholar 

  13. Cole, T.J. et al. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 9, 1608–1621 (1995).

    Article  CAS  Google Scholar 

  14. Edwards, A.V. Jones, C.T. The effect of splanchnic nerve section on the sensitivity of the adrenal cortex to adrenocorticotrophin in the calf. J. Physiol. 390, 23–31 (1987).

    Article  CAS  Google Scholar 

  15. Bornstein, S.R. Ehrhart-Bornstein, M. Scherbaum, W.A. Pfeiffer, E.F. Holst, J.J. Effects of splanchnic nerve stimulation on the adrenal cortex may be mediated by chromaffin cells in a paracrine manner. Endocrinol. 127, 900–906 (1990).

    Article  CAS  Google Scholar 

  16. Stenzel-Poore, M.P. Heinrichs, S.C. Rivest, S. Koob, G.F. Vale, W.W. Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J. Neurosci. 14, 2579–2584 (1994).

    Article  CAS  Google Scholar 

  17. Conti, L.H. et al. Mouse strain differences in the behavioral effects of corticotropin-releasing factor (CRH) and the CRH antagonist α-helical CRH9-41. Pharmacol. Biochem. Behav. 48, 497–503 (1994).

    Article  CAS  Google Scholar 

  18. Moreau, J.L. Kilpatrick, G. Jenck, F. Urocortin, a novel neuropeptide with anxiogenic-like properties. Neuroreport 8, 1697–1701 (1997).

    Article  CAS  Google Scholar 

  19. Liebsch, G. et al. Chronic infusion of a CRH1 receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats. Regul. Pept. 59, 229–239 (1995).

    Article  CAS  Google Scholar 

  20. Koob, G.F. Drug addiction: the yin and yang of hedonic homeostasis. Neuron 16, 893–896 (1996).

    Article  CAS  Google Scholar 

  21. Rassnick, S. Heinrichs, S.C. Britton, K.T. Koob, G.F. Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal. Brain Res. 605, 25–32 (1993).

    Article  CAS  Google Scholar 

  22. Tabakoff, B. Hoffmann, P.L. Alcohol addiction: An enigma among us. Neuron 16, 909–912 (1996).

    Article  CAS  Google Scholar 

  23. Evans, G.A. Lewis, K. Rothenberg, B.E. High efficiency vectors for cosmid microcloning and genomic analysis. Gene 79, 9–20 ( 1989).

    Article  CAS  Google Scholar 

  24. Tybulewicz, V.L. Crawford, C.E. Jackson, P.K. Bronson, R.T Mulligan, R.C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-ab1 proto-oncogene. Cell 65,1153 –1163 ( 1991).

    Article  CAS  Google Scholar 

  25. Wurst, W. Joyner, A.L. Production of targeted embryonic stem cell clones.in Gene Targeting, A Practical Approach (ed. Joyner, A.L.) 33–61 (IRL Press, Oxford, 1993).

    Google Scholar 

  26. Stalla, G.K. et al.Ketoconazole inhibts corticotropic cell function in vitro. Endocrinol. 122, 618–623 ( 1988).

    Article  CAS  Google Scholar 

  27. Karanth, S. et al. Hypothalamic-pituitary-adrenocortical axis changes in a transgenic mouse with impaired glucocorticoid receptor function. Endocrinol. 138, 3476–3485 (1997).

    Article  CAS  Google Scholar 

  28. Kresse, A. Jacobowitz, D.M. Skofitsch, G. Detailed mapping of CGRP mRNA expression in the rat central nervous system: Comparison with previous immunocytochemical findings. Brain Res. Bull. 36, 261–274 ( 1995).

    Article  CAS  Google Scholar 

  29. Spanagel, R. Putzke, J. Stefferl, A. Schö,B. Zieglgängsberger, W. Acamprosate and alcohol: II. Effects on alcohol withdrawal in the rat. Eur. J. Pharmacol. 305, 45–50 (1996).

    Article  CAS  Google Scholar 

  30. Crabbe, J.C. et al. Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors. Nature Genet. 14, 98–101 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank J. Favor for analysis of the eyes, O.F.X. Almeida, L. Bally-Cuif and R. Landgraf for critically reviewing the manuscript, A. Yassouridis for statistical analysis, A. Seasholtz, M. Stenzel-Poore, J. Arriza, R. Miesfeld and Y.-A. Barde for the generous gift of cDNA probes; S. Bourier, P. Westphal, P. Surbir, S. Bicking, T. Pohl, J. Stalla and C. Weis for excellent technical assistance, and S. Rengsberger for preparing the manuscript. This work was supported by a grant from the Volkswagen Foundation (F.H. and W.W.) and the Bundesministerium für Bildung und Forschung (R.S.).

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  1. Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich, D-80804, Germany

    Peter Timpl, Rainer Spanagel, Inge Sillaber, Adelheid Kresse, Johannes M. H. M. Reul, Günter K. Stalla, Veronique Blanquet, Thomas Steckler, Florian Holsboer & Wolfgang Wurst

  2. GSF Research Centre, Institute for Mammalian Genetics, Ingolstädter Landstr. 1, Munich, D-85764, Germany

    Veronique Blanquet & Wolfgang Wurst

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Correspondence to Wolfgang Wurst.

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Timpl, P., Spanagel, R., Sillaber, I. et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet 19, 162–166 (1998). https://doi.org/10.1038/520

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