A single-day treatment with mifepristone is sufficient to normalize chronic glucocorticoid induced suppression of hippocampal cell proliferation.
BACKGROUND
Chronic stress or prolonged administration of glucocorticoids suppresses proliferation and/or survival of newborn cells in adult rat dentate gyrus. Earlier we showed that administration of the glucocorticoid receptor antagonist mifepristone during the final 4 days of a 21 days period of corticosterone treatment fully normalized the number of newborn cells. Here we aimed to better understand how mifepristone achieves this effect and questioned whether an even shorter (single day) mifepristone treatment (instead of 4 days) also suffices to normalize neurogenesis.


METHODS
We investigated various steps of the neurogenic process, using the immunohistochemical markers BrdU, doublecortin, proliferating cell nuclear antigen as well as glial fibrillary acidic protein, after 17 or 21 days of corticosterone (versus vehicle) treatment.


RESULTS
Corticosterone primarily attenuates the proliferation of cells which subsequently develop into neurons; this is fully reversed by mifepristone. Surprisingly, the corticosteroid effects on neurogenesis can even be fully re-set by a single-day treatment with mifepristone (on day 18), despite the continued corticosterone exposure on subsequent days.


CONCLUSIONS
Our results emphasize that studies into the therapeutical efficacy of new antidepressants, especially those targeting HPA-activity or the glucocorticoid receptor, should explore the possibility to reduce treatment duration.
Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
Pu
P
Hu
Charlotte
C
Oomen
Anne-Marie
AM
van Dam
Jordi
J
Wester
Jiang-Ning
JN
Zhou
Marian
M
Joëls
Paul J
PJ
Lucassen
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003345:Corticosterone / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D000089662:Doublecortin Protein; D005938:Glucocorticoids / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology*; D007150:Immunohistochemistry; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D005938:Glucocorticoids; D015735:Mifepristone; D003345:Corticosterone