January 2011 Regular Article Biol. Pharm. Bull.

34(1) 77—81 (2011) 77

Chronic Treatment with Imipramine and Lithium Increases Cell

Proliferation in the Hippocampus in Adrenocorticotropic Hormone-
Treated Rats
Yoshihisa KITAMURA,*,a Maho DOI,a Keiko KUWATSUKA,a Yuka ONOUE,a Ikuko MIYAZAKI,b
Kazuaki SHINOMIYA,a Toshihiro KOYAMA,a Toshiaki SENDO,c Hiromu KAWASAKI,d Masato ASANUMA,b
and Yutaka GOMITAe
a
Department of Pharmaceutical Care and Health Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical
Sciences, Okayama University; d Department of Clinical Pharmacology, Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, Okayama University; 1–1–1 Tsushima-naka, Kita-ku, Okayama 700–8530, Japan: b Department
of Brain Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University;
c
Department of Pharmacy, Okayama University Hospital; 2–5–1 Shikata-cho, Kita-ku, Okayama 700–8558, Japan: and
e
Shujitsu University School of Pharmacy; 1–6–1 Nishinakagawara, Naka-ku, Okayama 703–8516, Japan.
Received August 26, 2010; accepted October 27, 2010; published online October 29, 2010

Adult hippocampal neurogenesis is reported to change in animal models of depression and antidepressants.
We have used the mitotic marker 5-bromo-2-deoxyyridine to address the effects of imipramine and lithium on
cell proliferation and survival following chronic treatment with adrenocorticotropic hormone (ACTH) in the
subgranular zone of the hippocampal dentate gyrus. ACTH treatment for 14 d decreased adult hippocampal cell
proliferation and survival. Coadministration of imipramine and lithium for 14 d blocked the loss of cell prolifer-
ation but not cell survival resulting from the chronic treatment with ACTH. The coadministration of imipramine
and lithium may have treatment-resistant antidepressive properties, which may be attributed, in part, to a nor-
malization of hippocampal cell proliferation.
Key words adrenocorticotropic hormone; imipramine; lithium; cell proliferation, 5-bromo-2-deoxyyridine

Major depressive disorder is a debilitating potentially fatal
illness with greater than 15% lifetime prevalence in the U.S.
population.1) Depression currently ranks among the top ten
causes of disability among the world’s population.2) Psy-
choendocrinological studies have focused on the regulation
of the hypothalamic-pituitary-adrenal (HPA) axis in patients
with depression.3,4) Cortisol hypersecretion in depression is
believed to result from abnormalities in the HPA axis.3) Mul-
tiple neuroendocrinological abnormalities appear in subjects
with depressive disorders, including increases in cortisol
secretion and the attenuation of cortisol suppression in
response to dexamethasone.5) Patients with Cushing’s disease,
a hyperadrenocorticism following a pituitary tumor, an adre-
nal tumor, or a tumor producing ectopic adrenocorticotropic
hormone (ACTH), often exhibit mental changes including
depression.6,7) Tricyclic antidepressants are not effective for
the treatment of depression in patients with Cushing’s dis-
ease, but steroid-suppressive agents such as metyrapone and
aminogluethimide are suggesting an etiological link between
depressive illness and the disinhibition of the HPA axis
observed in subjects with Cushing’s disease.8) In addition,
steroid-suppressive agents, such as metyrapone and keto-
conazole, and the glucocorticoid receptor antagonist RU486
are effective against antidepressant treatment-resistant
depression.7,9,10) These results suggest that abnormal activa-
tion of the HPA axis correlates with treatment-resistant
depression.
Furthermore, there are a number of similarities between
features of depression and chronic glucocorticoid administra-
tion in laboratory animals. We previously reported that the
chronic administration of ACTH to rats counteracted the
decrease in immobility time induced by a tricyclic antide-
pressant, imipramine or desipramine, in the forced swim test,
∗ To whom correspondence should be addressed. e-mail: ykita@pharm.okayama-u.ac.jp
which is widely used as a predictor of antidepressant
activity.11) Chronic coadministration of lithium, an agent that
potentiates the actions of antidepressants in patients with de-
pression, including those with treatment-resistant depression,
significantly decreased the duration of immobility, even
when given concurrently with ACTH.11) Chronic treatment of
rats with ACTH may therefore be an effective model of tri-
cyclic antidepressant treatment-resistant conditions.
Chronic treatment with antidepressants may increase cell
proliferation and cell survival and reverse stress-induced de-
creases in hippocampal cell proliferation and neurogene-
sis.12,13) The ability to promote hippocampal neurogenesis is
a feature of both classical antidepressants, such as tricyclic
drugs and selective serotonin re-uptake inhibitors.14,15) More-
over, hippocampal cell proliferation and neurogenesis might
be key factors in the actions of antidepressant drugs. We pre-
viously reported that the chronic administration of ACTH
(100 m g/rat, subcutaneously (s.c.), 14 d) significantly de-
creased the number of Ki-67 (an endogenous marker of cell
proliferation)-positive cells compared with the control value
in the subgranular zone (SGZ) of the hippocampal dentate
gyrus.16) This effect was not influenced by the chronic ad-
ministration of imipramine or lithium, but was reversed by
the coadministration of imipramine and lithium for 14 d in
ACTH-treated rats. The present study was undertaken to de-
termine the effect of chronic imipramine and lithium treat-
ment on adult hippocampal cell proliferation and survival,
quantified using 5-bromo-2-deoxyuridine (BrdU) immuno-
chemistry in the SGZ of ACTH-treated rats.
MATERIALS AND METHODS
Animals Male Wistar rats (Charles River, Yokohama,
© 2011 Pharmaceutical Society of Japan
78
Fig. 1. Time Schedule for the Administration of Drugs and BrdU
(A) Rats received imipramine (10 mg/kg) and lithium (100 mg/kg) once daily for
14 d, followed by BrdU (75 mg/kg, 4 times) and perfusion. (B) Rats received BrdU
(75 mg/kg, 4 times) on Day 1 followed by imipramine (10 mg/kg) and lithium
(100 mg/kg) for 14 d after the last BrdU administration.
Japan) with an initial weight of 220—230 g were utilized.
The rats were group-housed, 4 per cage, under a constant
light–dark cycle (lights on, 07:00—19:00) and fed standard
laboratory food and tap water in an air-conditioned room
(231 °C with approximately 60% humidity). All experi-
ments were conducted according to the guidelines for animal
experimentation at Okayama University Medical School.
Every effort was made to minimize the number and suffering
of the animals used. Five animals were used for each group.
Drugs The following drugs were used: imipramine hy-
drochloride (Sigma), lithium carbonate (Taisho Pharmaceuti-
cal, Tokyo, Japan) and ACTH-(1-24)-zinc (Cortrosyn-Z: Dai-
ichi-Sankyo, Tokyo, Japan). Imipramine was dissolved in
saline. Lithium was suspended in a 0.5% methylcellulose so-
lution. The rats were administered imipramine and lithium at
a dosage of 2 ml/kg of body weight for 14 d. ACTH
(Cortrosyn-Z) was injected subcutaneously once daily (09:00
to 10:00 h) at 100 m g/rat (the injection volume was
0.2 ml/rat) for 14 d. The control rats received an equivalent
volume of vehicle (saline 0.2 ml/rat) subcutaneously for the
same period of time. The thymidine-analog 5-bromo-2-de-
oxyuridine (BrdU) (Sigma Aldrich, St. Louis, MO, U.S.A.) is
incorporated into dividing cells during the S-phase and thus
serves as a marker for cell proliferation. BrdU (75 mg/kg)
was administered intraperitoneally, 4 times per day, at 6-h in-
tervals (10.00 a.m., 4.00 p.m., 10.00 p.m., 4.00 a.m.). In the
proliferation experiment, BrdU was given during the last 14 d
of the drug-treatment period. To try to separate the effects on
cell proliferation and survival of ACTH, imipramine, or
lithium, BrdU was given during the 14 d prior to treatment in
the survival experiment (Fig. 1).
Immunohistochemistry Six hours (proliferation experi-
ment) or 14 d (survival experiment) after the last BrdU-injec-
tion, rats were transcardially perfused with ice-cold saline
followed by a fixative containing 4% paraformaldehyde and
0.35% glutaraldehyde in 0.1 M phosphate buffer (PB, pH 7.4)
under deep anesthesia with pentobarbital sodium (80 mg/kg,
intraperitoneally (i.p.)). After the perfusion, the brain was
rapidly removed en bloc from the skull, post-fixed for 24 h in
a fixative containing 4% paraformaldehyde in 0.1 M PB (pH
7.4), and cryoprotected in 20% sucrose in 0.1 M PB with
sodium azide. Brains snap-frozen with powdered dry ice
were cut coronally on a cryostat into 20-m m thick sections
containing the dentate gyrus of the hippocampus. The sec-
Vol. 34, No. 1
tions were collected in 10 mM phosphate-buffered saline
(PBS) with 0.1% sodium azide for staining. Standard free-
floating immunohistochemistry was used to detect BrdU-im-
munopositive signals in the dentate gyrus. Free-floating sec-
tions were subjected to deoxyribonucleic acid denaturation
by incubation for 2 h in 50% formamide/2standard saline
citrate (SSC) at 65 °C, followed by a 2SSC rinse. Sections
were incubated for 20 min in 2 N HCl, PBS, and for 15 min in
0.1 M boric acid, pH 8.5. After incubation in 1% normal goat
serum for BrdU in PBST (10 mM PBS containing 0.2% Tri-
ton X-100) for 30 min, the sections were exposed to a rat
anti-BrdU monoclonal antibody (diluted 1 : 1000 in PBST;
abcam, Cambridge, MA, U.S.A.) for 18 h at 4 °C. The sec-
tions were then washed in PBST (55 min) and incubated
with a goat anti-rat immunoglobulin G (IgG) Alexa Fluor
488 antibody (diluted 1 : 1000 in PBST; Invitrogen, Carlsbad,
CA, U.S.A.) for 2 h at room temperature. All slides were ana-
lyzed under a fluorescence microscope (Olympus BX50-
FLA; Olympus, Tokyo, Japan) using a mercury lamp through
a 470—490 nm band-pass filter to excite the Alexa Fluor
488. The light emitted from Alexa Fluor 488 was collected
through a 515—550 nm band-pass filter or 470—490 nm
long-pass filter. The stained cells were photographed at a
magnification of 200. For each brain, serial sections were
collected to generate five sets representative of the entire hip-
pocampus (2.3 mm to 4.3 mm from bregma). Each set
contained sections at least 20 m m thick (400 m m apart) cover-
ing the entire anteroposterior extent of the hippocampus.
Then the mean count obtained was multiplied by 5 (the num-
ber of series) to obtain an estimate of the total number of
BrdU-positive cells throughout the dentate gyrus. The BrdU-
positive cells of the dentate gyrus were counted by an investi-
gator blinded to the experiments.
Statistical Analysis All values are expressed as the
group meanS.E.M. Means were compared using Tukey’s
test for multiple comparisons.
RESULTS
Effects of Chronic Treatment with Imipramine and
Lithium for 14 d on Cell Proliferation in the SGZ of the
Hippocampal Dentate Gyrus in Saline and ACTH-
Treated Rats The administration of neither imipramine
(10 mg/kg, i.p.) nor chronic lithium (100 mg/kg, per os
(p.o.)) for 14 d affected the number of BrdU-positive cells in
the SGZ of the hippocampal dentate gyrus. The coadmin-
istration of imipramine (10 mg/kg, i.p.) and lithium
(100 mg/kg, p.o.) for 14 d did not change the number either
(Fig. 2A). Treatment with ACTH (100 m g/rat, s.c.) for 14 d
significantly decreased the number (Fig. 2B). This effect was
not influenced by the chronic administration of imipramine,
but was reversed by the administration of lithium, and signif-
icantly reversed by the coadministration of imipramine and
lithium for 14 d (Fig. 2B).
Effects of Chronic Treatment with Imipramine and
Lithium for 14 d on the Survival of Newborn Cells in the
SGZ of the Hippocampal Dentate Gyrus in Saline and
ACTH-Treated Rats The administration of neither
imipramine (10 mg/kg, i.p.) nor lithium (100 mg/kg, p.o.) for
14 d affected the number of BrdU-positive cells in the SGZ
of the hippocampal dentate gyrus. The coadministration of
January 2011
Fig. 2. Effects of Chronic Treatment with Imipramine and Lithium for
14 d on Cell Proliferation in the SGZ of the Hippocampal Dentate Gyrus in
Saline-Treated (A) and ACTH-Treated (B) Rats
Rats were administered imipramine (IMI: 10 mg/kg), lithium (LI: 100 mg/kg) and
ACTH (100 m g/rat) once daily for 14 d. On the 15th day, BrdU was administered in-
traperitoneally, 4 times at 6-h intervals. (C) Representative fluorescence photomicro-
graphs of the effect of imipramine and lithium on the number of BrdU-positive cells in
the SGZ of the hippocampal dentate gyrus in ACTH-treated rats. Values are expressed
as the meanS.E.M. for 5 animals. Data were analyzed with a one-way ANOVA, fol-
lowed by Tukey’s test. ∗∗ p0.01, significantly different from the control value.
## p0.01, significantly different from the ACTH value.
imipramine (10 mg/kg, i.p.) and lithium (100 mg/kg, p.o.) for
14 d did not change the number either (Fig. 3A). Treatment
with ACTH (100 m g/rat, s.c.) for 14 d significantly decreased
the number (Fig. 3A). This effect was not influenced by the
chronic administration of imipramine or lithium or the coad-
ministration of imipramine and lithium for 14 d (Fig. 3B).
DISCUSSION
We observed that chronic ACTH treatment resulted in a
decrease in cell proliferation and survival in the SGZ of the
hippocampal dentate gyrus, whereas the coadministration of
imipramine and lithium increased neurogenesis in ACTH-
treated rats. We previously found that plasma corticosterone
levels were significantly higher in rats treated with ACTH for
79
Fig. 3. Effects of Chronic Treatment with Imipramine and Lithium for
14 d on Cell Survival in the SGZ of the Hippocampal Dentate Gyrus in
Saline-Treated (A) and ACTH-Treated (B) Rats
On the first day, BrdU was administered intraperitoneally, 4 times at 6-h intervals.
Rats were administered imipramine (IMI: 10 mg/kg), lithium (LI: 100 mg/kg) and
ACTH (100 m g/rat) once daily for 14 d. (C) Representative fluorescence photomicro-
graphs of the effect of imipramine and lithium on the number of BrdU-positive cells in
the SGZ of the hippocampal dentate gyrus in ACTH-treated rats. Values are expressed
as the meanS.E.M. for 5 animals. Data were analyzed with a one-way ANOVA, fol-
lowed by Tukey’s test. ∗∗ p0.01, significantly different from the control value.
14 d (100 m g/d, s.c.) than in saline-treated rats (saline:
1.10.2 mg/dl; 14 d: 13.93.0 mg/dl). We thereby demon-
strated that chronic ACTH treatment produced a significant
elevation in corticosterone levels, a condition termed hyper-
corticism. Given the repetitive activation of the HPA axis, it
seems probable that glucocorticoids play an important role in
the development of aberrant brain functions after chronic
ACTH treatment, e.g., in the suppression of cell proliferation
and neurogenesis. It has been reported that a glucocorticoid
receptor antagonist ameliorated the depressive effects of
chronic stress on adult neurogenesis.17) In the present study,
chronic ACTH treatment led to strong activation of the HPA
axis, suggesting reductions in adult hippocampal cell prolif-
eration and survival.
We found that the cell survival in the SGZ of the hip-
80
pocampal dentate gyrus was decreased compared to cell pro-
liferation in saline-treated rats. It was reported that only
about half of newly formed cells survived 28 d in the rat.18)
Furthermore, indirect evidence of the death of new neurons
has come from studies showing a decrease in the number of
new cells in the adult dentate gyrus between 1 week and 2
weeks after labeling with BrdU or [3H]-thymidine.19,20)
Namely, our finding was consistent with previous reports.
Furthermore, we previously stained tissue sections with anti-
bodies directed against the endogeneous proliferation antigen
Ki-67.16) Since this antigen is expressed only during cell divi-
sion, Ki-67-staining detects only cells proliferating at the
time of perfusion. It was found that the chronic administra-
tion of ACTH (100 m g/d, s.c.) significantly decreased the
number of Ki-67-positive cells compared with the control in
the SGZ of the hippocampal dentate gyrus.16) Namely, activa-
tion of the HPA axis can result in a marked suppression of
cell proliferation. From BrdU-labeling on the last day, we
confirmed that ACTH treatment reduces the number of
BrdU-positive cells in the SGZ of the dentate gyrus. In this
study, we verified that BrdU-labeling on the final day of drug
administration reflects newly formed (BrdU-labeled) cells.
Chronic ACTH treatment decreased the number of BrdU-
positive cells in the SGZ. The results show that the reduction
in BrdU-positive cells seen after ACTH treatment reflects a
reduction in cell proliferation.
Several studies have shown an increase in hippocampal
cell proliferation and neurogenesis in rodents following
chronic treatment with antidepressants such as fluoxetine (a
selective serotonin re-uptake inhibitor), imipramine, and de-
sipramine (tricyclic antidepressants).15) On the other hand, a
decrease in cell proliferation and neurogenesis in the dentate
gyrus of the hippocampus has been demonstrated in different
animal models of depression.12,13) It has also been shown that
stress-induced changes in the levels of hippocampal cell pro-
liferation and neurogenesis can be reversed by the chronic
administration of antidepressants.21—23) We previously found
that the effect of the chronic administration of imipramine
(10 mg/kg, i.p., 14 d) on immobility time during the forced
swim test was inhibited by chronic treatment with ACTH in
rats.11) In the present study, neither imipramine nor lithium
alone affected the number of BrdU-positive cells in the SGZ
in saline-treated rats. However, the coadministration of
imipramine and lithium for 14 d significantly increased the
number of BrdU-positive cells in ACTH-treated rats. The in-
hibition of the immobility-decreasing effect of imipramine
(10 mg/kg, i.p., 14 d) is reversed by coadministration of
imipramine (10 mg/kg, i.p., 14 d) and lithium (100 mg/kg,
p.o., 14 d). Namely, it seems that antidepressive-like effects
are related to cell proliferation in the SGZ of the dentate
gyrus.
In the central nervous system, lithium alters the dynamics
of neurotransmission within serotonergic pathways. In bio-
chemical studies with rats, lithium increased 5-HT’s synthe-
sis in the brain, 5-HT’s turnover in various regions of the
brain, and 5-HT’s release from nerve endings.24,25) On the
other hand, some clinical studies have demonstrated in-
creases in the number of 5-HT2A receptor-binding sites in
postmortem brains of both suicides and depressed subjects.
We previously reported that chronic ACTH treatment poten-
tiated ()-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
Vol. 34, No. 1
(DOI)-induced wet-dog shakes, via the activation of 5-HT2A
receptors. Furthermore, the enhancing effect on DOI-induced
wet-dog shakes was blocked by the coadministration of
lithium and imipramine, but not by imipramine alone.26) Jha
et al. reported that chronic administration of ketanserin, a 5-
HT2A receptor antagonist, reduced the expression of the 5-
HT2A receptor.27) Namely, it is possible that the inhibition of
5-HT2A receptor function enhances cell proliferation in the
SGZ of the hippocampal dentate gyrus. More studies are re-
quired to clarify whether the effect of 5-HT2A receptors the
adult hippocampal progenitors is direct or indirect. Further-
more, the possibility that the noradrenergic system is in-
volved in the effects observed in the present study could not
be excluded. Studies are underway to clarify the serotonergic
and noradrenergic functions upon the coadministration of
imipramine and lithium in chronic ACTH-treated rats.
Treatment with ACTH for 14 d decreased cell survival in
the SGZ of the hippocampal dentate gyrus. This decrease
was not blocked by imipramine and lithium. Previous re-
search has suggested that antidepressants may promote cell
survival in the dorsal hippocampus.28,29) Interestingly, in-
creases in cell survival were not observed in the present
study, suggesting that imipramine and lithium regulate cell
proliferation independently of cell survival. Indeed, the mag-
nitude of the effect of imipramine and lithium on prolifera-
tion surpassed that on cell survival, suggesting that
imipramine and lithium increase neurogenesis mainly by in-
creasing proliferation.
To conclude, this study demonstrated that chronic ACTH
treatment inhibited cell proliferation and survival in the SGZ
of the hippocampal dentate gyrus. In addition, imipramine
and lithium affected cell proliferation in ACTH-treated rats.
Combined with previous findings of cell proliferation in the
adult hippocampus, these results support the notion that
imipramine and lithium would improve the efficacy of treat-
ment for resistant depression by triggering cell proliferation.
Acknowledgments This study was supported in part by
a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan (No. 21590593).
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