Brief Treatment With the Glucocorticoid Receptor Antagonist
Mifepristone Normalises the Corticosterone-Induced Reduction of Adult
J. L. Mayer,*? L. Klumpers,* S. Maslam,* E. R. de Kloet,? M. Joe ¨ls* and P. J. Lucassen*
*Swammerdam Institute for Life Sciences, Centre for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
?Division Medical Pharmacology, LACDR, Leiden University Medical Center, Leiden, The Netherlands.
Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis is
common during depression. Symptoms can include elevated cortisol
levels that affect hippocampal function and structure (1–4). In
rodents, stress and elevated corticosterone (CORT) concentrations
suppress adult neurogenesis (5–7). Although it has not yet been
directly observed (8–10), it is hypothesised that similar reductions
in neurogenesis occur in humans, which might contribute to the
hippocampal volume reductions observed in depression (2, 8–13).
Additionally, the loss of hippocampal neurogenesis in rodents nulli-
fies the behavioural effects of current antidepressants (12). In sup-
port of a role for the HPA axis in depression (1, 2), recent clinical
studies have shown that the glucocorticoid-receptor (GR) antagon-
ist mifepristone relieves symptoms of psychotic depression after a
remarkably brief treatment period of 4 or 8 days (14–16). We
hypothesised that GR-blockade would normalise chronic CORT-
induced changes in hippocampal neurogenesis.
Significant increases in morning plasma CORT concentrations in
the CORT (P ¼ 0.014) and mifepristone + CORT (RC) (P ¼ 0.044)
groups (Fig. 1) were observed in different but identically treated
animals (n ¼ 13 per group). Thymus- and adrenal-weights were
reduced in the CORT group (P ¼ 0.0004). CORT-animals also had
significantly decreased 5-bromo-2-deoxyuridine (BrdU) cell numbers
(RU38486) + CORT (RC) animals, mifepristone-treatment normalised
this reduction back to control levels. CORT animals also had a
reduction in doublecortin- (DCX) (17) labelled cell numbers (F3,18¼
P ¼ 0.014),whereas,inmifepristone
6.219, P ¼ 0.006), a measure of neurogenesis independent of BrdU,
with DCX cells once again normalised in the RC group (F3,22¼
4.609, P ¼ 0.014). No changes were found for Ki-67.
We conclude that a 4-day mifepristone treatment rapidly nor-
malises the chronic CORT-induced suppression of adult neurogene-
sis (Fig. 1). Interestingly, this time frame parallels the 4-day RU486
treatment regimen that is effective in patients suffering from psy-
chotic depression (14–16). Mifepristone alone had no effect but
exerted normalising effects in rats receiving concomitant CORT
treatment. This indicates that the cellular effects of mifepristone
are particularly potent in a high CORT environment and differ from
other antidepressants, which increase adult neurogenesis at both
basal and elevated CORT levels (10–13, 19). Mifepristone acts by
binding to GRs that are normally only fully occupied when circula-
ting CORT levels are elevated. Thus, mifepristone may exert its nor-
malising effect by blocking CORT from occupying hippocampal GRs,
thereby preventing a putative decrease in adult neurogenesis. Addi-
tionally, blockade of GRs may alter function of the mineralocorti-
coid receptor, which is implicated in HPA axis regulation and
cytogenesis (1, 18, 19).
Mifepristone treatment normalised both neurogenesis (DCX) and
survival (BrdU), but did not affect proliferation (Ki-67). The current
changes in DCX were paralleled by changes in BrdU, suggesting
that cell number is directly affected. Dissociations between different
stages of adult neurogenesis have been observed previously (5–7,
18, 20) and may be a result of major variations in the sensitivity of
Dr Paul J. Lucassen, Swammerdam
Institute for Life Sciences, Centre for
Neuroscience, University of
Amsterdam, Kruislaan 320, 1098 SM,
Amsterdam, The Netherlands (e-mail:
The glucocorticoid receptor antagonist mifepristone has been shown to rapidly and effectively
ameliorate symptoms of psychotic major depression. To better understand its mechanism, we
investigated mifepristone’s cellular effects, and found that it rapidly reversed a chronic corticos-
terone-induced reduction of adult neurogenesis in rats. Unlike other antidepressants, mifepri-
stone is particularly potent in a high corticosterone environment. These data indicate that
similarly to its clinical efficacy, mifepristone’s effects on adult neurogenesis are rapid and posit-
ive, and may therefore be important for its mechanism of action.
Key words: depression, stress, neurogenesis, RU38486, doublecortin.
Journal of Neuroendocrinology 18, 629–631
ª 2006 The Authors. Journal Compilation ª 2006 Blackwell Publishing Ltd
progenitor cells, versus young or mature neurones, to the local cor-
ticoid environment. Also, differences in BrdU injections and survival
time may be involved (7, 17, 18, 20). Contrary to young neurones,
newly formed, proliferating cells only express low and variable lev-
els of GRs (21), which may explain the lack of effect of CORT and
mifepristone on proliferation (18, 20, 21).
In the present study, CORT was administered for 21 days because
chronic exposure is required to affect hippocampal plasticity (1, 2,
4, 6). Most antidepressants generally need a minimal period of
3–4 weeks to relieve depression in patients (9, 11). In animals, these
antidepressants affect adult neurogenesis over the same 3–4-week
time period. By contrast, we observed a full reversal after only
4 days of treatment. This points to a ‘rescue’ effect of a population
that otherwise may have been lost, especially in conjunction with
previous findings of distinct stages of the neurogenic process (7,
18). Indeed, the population of immature DCX-positive cells can
expand several-fold within a few days, and already has some func-
tional properties (7, 17). Although we cannot speculate on whether
the present changes are paralleled in humans, rescuing this rapidly
maturing cell population may potentially contribute to an antide-
pressant effect. For both mifepristone and other antidepressants,
the time-course of neurogenesis effects matches the time-to-effect
Fig. 1. Twenty-eight Wistar rats were divided into a corticosterone (CORT) only, mifepristone (RU38486) + CORT (RC), mifepristone-only (RO) and vehicle (VEH)
(arachidus-oil) group. CORT and RC groups were injected s.c. with CORT in arachidus-oil daily at 09.00 h for 21 days (10 mg⁄kg). On day 1 of the 21-day
time-course (3 h following the first CORT or vehicle injections), all animals received 5-bromo-2-deoxyuridine (BrdU) i.p. (200 mg⁄kg body weight). This caused
all BrdU incorporation to occur during elevated CORT conditions, thereby ensuring an optimal distinction between the groups and reducing variation in BrdU
number. On days 18–21, at 09.00 h and 16.00 h, RC and RO-animals received mifepristone (5 mg⁄100 g body weight; Mifepristone, Sigma, St Louis, MO, USA)
dissolved in 30 ll ethanol⁄1.5 ml coffee creamer (Campina, Woerden, The Netherlands), which was administered through an oral syringe directly into the stom-
ach. Fourteen-hours after their final mifepristone treatment, animals (then 10 weeks old) were perfused (6). We intentionally avoided the stereology method
that generates data with high variance (18) and quantified all BrdU+ (survival), Ki-67+ (proliferation) and doublecortin (17) (DCX)+ cells (dilution 1 : 1000;
Santa Cruz Biotechnology, Santa Cruz, CA, USA) in randomised and coded 40-lm sections from a systematically sampled 1-in-10 series through the entire uni-
lateral dentate gyrus. Data shown reflects mean counts. ANOVA and post-hoc Student’s t-test were used for statistical analysis. (A) Representative BrdU+ cells in
the granule cell layer (GCL). (B) Few DCX+ neurones, frequent empty gaps (asteriks) and short extensions (arrow) are found in CORT-treated animals. (C) Promin-
ent DCX expression with extensions into the GCL (arrowheads) occurs in VEH and RU + CORT-treated animals. (D) Mifepristone normalises CORT-induced reduc-
tions in newborn cell survival (BrdU) and (E) neurogenesis (DCX). *P < 0.05.
J. L. Mayer et al
ª 2006 The Authors. Journal Compilation ª 2006 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 18, 629–631
for clinical efficacy in treating depression. This further stresses the
importance of timing in the treatment of depression and indirectly
supports the notion that clinical effect of antidepressants may be
linked to their cellular effects (2, 8–13).
In conclusion, brief treatment with mifepristone reverses the
reduction in adult neurogenesis after chronic CORT treatment. This
cellular effect parallels findings for various other antidepressants.
The assistance of Dr E. Van Riel is greatly appreciated. J.L.M. is supported
by Corcept Therapeutics, Inc. P.J.L. is supported by the VolkwagenStiftung,
Germany and the HersenStichting Nederland.
Accepted 26 May 2006
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