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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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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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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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