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Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression

Molecular Psychiatry volume 9, pages 278–286 (2004)Cite this article

Abstract

Repeated exposure to stress is known to induce structural remodelling and reduction of neurogenesis in the dentate gyrus. Corticotrophin-releasing factor (CRF) and vasopressin (AVP) are key regulators of the stress response via activation of CRF1 and V1b receptors, respectively. The blockade of these receptors has been proposed as an innovative approach for the treatment of affective disorders. The present study aimed at determining whether the CRF1 receptor antagonist SSR125543A, the V1b receptor antagonist SSR149415, and the clinically effective antidepressant fluoxetine may influence newborn cell proliferation and differentiation in the dentate gyrus of mice subjected to the chronic mild stress (CMS) procedure, a model of depression with predictive validity. Repeated administration of SSR125543A (30 mg/kg i.p.), SSR149415 (30 mg/kg i.p.), and fluoxetine (10 mg/kg i.p.) for 28 days, starting 3 weeks after the beginning of the stress procedure, significantly reversed the reduction of cell proliferation produced by CMS, an effect which was paralleled by a marked improvement of the physical state of the coat of stressed mice. Moreover, mice subjected to stress exhibited a 53% reduction of granule cell neurogenesis 30 days after the end of the 7-week stress period, an effect which was prevented by all drug treatments. Collectively, these results point to an important role of CRF and AVP in the regulation of dentate neurogenesis, and suggest that CRF1 and V1b receptor antagonists may affect plasticity changes in the hippocampal formation, as do clinically effective antidepressants.

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Acknowledgements

We thank M Fournier, C Aliaga, H Lacroix, and Y Biron for technical assistance, and J Alexander for critical reading of the manuscript.

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Authors and Affiliations

  1. Sanofi-Synthelabo Recherche, Rue du Professeur J. Blayac, Montpellier, France

    R Alonso, G Pavone & P Soubrié

  2. Avenue P.V. Couturier, Bagneux, France

    G Griebel & J Stemmelin

  3. Avenue de France, Paris, France

    G Le Fur

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Correspondence to R Alonso.

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Alonso, R., Griebel, G., Pavone, G. et al. Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression. Mol Psychiatry 9, 278–286 (2004). https://doi.org/10.1038/sj.mp.4001464

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