Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress

Authors

  • Charlotte A. Oomen,

    1. SILS Centre for Neuroscience, University of Amsterdam, Kruislaan 320, 1098 SM, Amsterdam, the Netherlands
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    • *

      C.A.O. and J.L.M. contributed equally to this work

  • Joseph L. Mayer,

    1. SILS Centre for Neuroscience, University of Amsterdam, Kruislaan 320, 1098 SM, Amsterdam, the Netherlands
    2. Division Medical Pharmacology, LACDR, Leiden University Medical Center, the Netherlands
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    • *

      C.A.O. and J.L.M. contributed equally to this work

  • E. Ronald De Kloet,

    1. Division Medical Pharmacology, LACDR, Leiden University Medical Center, the Netherlands
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  • Marian Joëls,

    1. SILS Centre for Neuroscience, University of Amsterdam, Kruislaan 320, 1098 SM, Amsterdam, the Netherlands
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  • Paul J. Lucassen

    1. SILS Centre for Neuroscience, University of Amsterdam, Kruislaan 320, 1098 SM, Amsterdam, the Netherlands
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Dr Paul J. Lucassen, as above.
E-mail: lucassen@science.uva.nl

Abstract

In rodents, stress suppresses adult neurogenesis. This is thought to involve activation of glucocorticoid receptors in the brain. In the present study, we therefore questioned whether glucocorticoid receptor blockade by mifepristone can normalize the effects of chronic stress on adult neurogenesis. Rats received mifepristone on the last 4 days of a 21-day chronic unpredictable and inescapable stress regimen. Neurogenesis was analysed by stereological quantification of adult-generated cell survival (bromodeoxyuridine), young neuronal survival (doublecortin) and cell proliferation (Ki-67). The results show that only 4 days of mifepristone treatment normalized the stress-induced reductions in neurogenesis. Importantly, mifepristone by itself had no effect on neurogenesis. We conclude that, contrary to other compounds interfering with the effects of chronic stress on neurogenesis, like antidepressants, the normalizing effects of mifepristone on neurogenesis are rapid and particularly potent in a high stress environment. This neurogenic action of mifepristone could potentially contribute to its clinical mechanism of action.

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