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J Neural Transm

DOI 10.1007/s00702-010-0451-2

BASIC NEUROSCIENCES, GENETICS AND IMMUNOLOGY - ORIGINAL ARTICLE

Chronic administration of harmine elicits antidepressant-like


effects and increases BDNF levels in rat hippocampus
Jucélia J. Fortunato • Gislaine Z. Réus • Tamires R. Kirsch • Roberto B. Stringari •

Gabriel R. Fries • Flávio Kapczinski • Jaime E. Hallak • Antônio W. Zuardi •


José A. Crippa • João Quevedo

Received: 13 April 2010 / Accepted: 12 July 2010


Ó Springer-Verlag 2010

Abstract A growing body of evidence has pointed to the (10 and 30 mg/kg) and harmine (5 and 10 mg/kg), without
b-carboline harmine as a potential therapeutic target for the affecting spontaneous locomotor activity. Brain-derived
treatment of major depression. The present study was neurotrophic factor (BDNF) hippocampal levels were
aimed to evaluate behavioural and molecular effects of the assessed in imipramine and harmine-treated rats by ELISA
chronic treatment with harmine and imipramine in rats. To sandwich assay. Interestingly, chronic administration of
this aim, rats were treated for 14 days once a day with harmine at the higher doses (10 and 15 mg/kg), but not
harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and imipramine, increased BDNF protein levels in rat hippo-
30 mg/kg) and then subjected to the forced swimming and campus. Finally, these findings further support the hypoth-
open-field tests. Harmine and imipramine, at all doses tested, esis that harmine could bring about behavior and molecular
reduced immobility time of rats compared with the saline effects, similar to antidepressants drugs.
group. Imipramine increased the swimming time at 20 and
30 mg/kg and harmine increased swimming time at all doses. Keywords Harmine  Imipramine 
The climbing time increased in rats treated with imipramine Forced swimming test  Monoamine oxidase  Depression

J. J. Fortunato  G. Z. Réus  T. R. Kirsch  Introduction


R. B. Stringari  J. Quevedo (&)
Laboratório de Neurociências and Instituto Nacional de Ciência
e Tecnologia Translacional em Medicina (INCT-TM), Programa Depression is a serious mental illness that affects approx-
de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica imately 17% of the population and is a major cause of
de Ciências da Saúde, Universidade do Extremo Sul Catarinense, disability worldwide. Findings from World Health Orga-
Criciúma, SC 88806-000, Brazil
nization predict that depression will be the leading cause of
e-mail: quevedo@unesc.net
disability and premature death in the industrial world by
G. R. Fries  F. Kapczinski the year 2020 (Mathers and Loncar 2006).
Laboratório de Psiquiatria Molecular and Instituto Nacional de Major depression encompasses a range of features,
Ciência e Tecnologia Translacional em Medicina (INCT-TM),
which include not only symptoms such as sleep and
Centro de Pesquisas, Hospital de Clı́nicas de Porto Alegre,
Porto Alegre, RS 90035-003, Brazil appetite disturbances (both up and down), loss of interest
and pleasure, negative rumination, fatigue, and poor con-
J. E. Hallak  A. W. Zuardi  J. A. Crippa centration, but also apparent abnormalities of the hypo-
Departamento de Neurociências e Ciências do Comportamento
thalamic–pituitary–adrenal axis or of neuroplasticity
and Instituto Nacional de Ciência e Tecnologia Translacional em
Medicina (INCT-TM), Faculdade de Medicina de Ribeirão (Garcia et al. 2008a, b, 2009; Lucca et al. 2008, 2009;
Preto, Universidade de São Paulo, Ribeirão Preto, SP 14049-900, Shelton 2007).
Brazil The clinically used antidepressants increase the extra-
cellular concentrations of monoamines, serotonin, or nor-
J. Quevedo
Laboratório de Psiquiatria Translacional, Centro De Pesquisa, epinephrine, either by inhibiting their reuptake from the
Hospital São José, Criciúma, SC 88801-250, Brazil synapse or by blocking their degradation by inhibiting

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J. J. Fortunato et al.

monoamine oxidase (Duman et al. 1997; Castrén 2005; Criciúma, SC, Brazil) breeding colony. They were housed
Nestler et al. 2002). However, antidepressants interact also five per cage with food and water available ad libitum and
with dopaminergic, melatoninergic, glutamatergic, or neu- were maintained on a 12-h light/dark cycle (lights on at
ropetide systems (for a review: Racagni and Popoli 2010). 7:00 a.m.). All experimental procedures involving animals
Preclinical findings suggest that beta-carboline harmine were performed in accordance with the NIH Guide for the
present antidepressant-like actions in rodents subjected to Care and Use of Laboratory Animals and the Brazilian
an animal model of depression (Farzin and Mansouri 2006; Society for Neuroscience and Behavior (SBNeC) recom-
Fortunato et al. 2009, 2010). In fact, studies have demon- mendations for animal care and with approval by local
strated that harmine interacts with monoamine oxidase A Ethics Committee under protocol number 325/2008.
(MAO-A) (Kim et al. 1997) and several cell-surface
receptors, including serotonin receptor 2A (5-HT2A) Drugs and treatments
(Glennon et al. 2000), which were related to antidepressant
pharmacotherapy (Preskorn et al. 2008). Moreover, we Harmine was obtained from THC-Pharm/STI-Pharm
recently demonstrated that acute treatment with harmine at (Frankfurt, Germany) and imipramine, the standard anti-
dose of 15 mg/kg increased BDNF protein levels in rat depressant, from Novartis Pharmaceutical Industry (Cri-
hippocampus (Fortunato et al. 2009). ciúma, Brazil). Different groups of rats (n = 15 each) were
A growing body of evidence has pointed to the role of administered intraperitoneally (IP) with saline or different
brain-derived-neurotrophic factor (BDNF) in major depres- doses of harmine (5, 10 and 15 mg/kg) or imipramine (10,
sion. Alterations of hippocampal structure and function in 20 and 30 mg/kg) during 14 days (Garcia et al. 2008b;
response to stress provided the rationale for analysis of Fortunato et al. 2009). Imipramine and harmine were dis-
neurotrophic factors (Duman and Monteggia 2006). solved in saline immediately before the IP injections. All
Decreased serum BDNF levels have been found in major treatments were administered in a volume of 1 ml/kg. Rats
depressed patients (Karege et al. 2002), whereas brain were tested in the open field and forced swim test following
infusion of BDNF produces antidepressant-like action in rats chronic imipramine and harmine treatments. Beginning on
(Shirayama et al. 2002; Siuciak et al. 1997). In addition, day 12 of chronic treatment, rats were tested in the open
exposure to stress decreases levels of BDNF in brain regions field. On day 13 and 14 of chronic treatment, rats were then
associated with depression, while antidepressant treatment tested in the forced swimming test. From day 12 to 14 of
produces opposite actions and blocks the effects of stress on chronic treatment, drug administration was done 60 min.
BDNF (for a review see: Duman and Monteggia 2006; before the assessment of animal behaviour in the open field
Kozisek et al. 2008). Interestingly, chronic, but not acute, (day 12) and forced swimming test (days 13 and 14).
antidepressant treatment induces increasing of BDNF
expression and BDNF immunoreactive fibers in rodent hip- Forced swimming test
pocampus (De Foubert et al. 2004; Nibuya et al. 1996). Thus,
agents capable of enhancing BDNF levels may lead in aiding The forced swimming test was conducted according to
the development of innovative antidepressant drugs (Garcia previous reports (Detke et al. 1995; Garcia et al. 2008a, b;
et al. 2008a; Zarate et al. 2006). Porsolt et al. 1977). The test involves two individual
Thus, the main objective of the present study was to exposures to a cylindrical tank with water in which rats
evaluate behavioral and molecular effects induced by cannot touch the bottom of the tank or escape. The tank is
chronic administration of harmine and imipramine in rats. made of transparent Plexiglas, 80 cm tall, 30 cm in diam-
The behavioral effects of both drugs were evaluated in the eter, and filled with water (22–23°C) to a depth of 40 cm.
forced swimming test, which is a valid behavioral despair On day 13 of chronic treatment, 1 h after drug treatment,
assay widely used for screening antidepressant drugs rats were individually placed in the cylinder containing
(McArthur and Borsini 2006). The BDNF protein levels water for 15 min. (pre-test session). On the 14th day, rats
were measured using an ELISA kit in rat hippocampus received the last IP drug treatment, and after 1 h, they were
chronically treated with harmine and imipramine. subjected again to the forced swimming test for a 5-min
session (test session). During the test session some
behavioural parameters were recorded in seconds, such as,
Materials and methods immobility time (i.e. no additional activity is observed
other than that required to keep the rat’s head above the
Animals water), climbing time, which is defined as upward-directed
movements of the forepaws along the side of the swim
Male Adult Wistar rats (60 days old) were obtained from chamber, and swimming time (i.e. movement usually
UNESC (Universidade do Extremo Sul Catarinense, horizontal throughout the swim chamber).

123
Chronic administration of harmine elicits antidepressant-like effects

Open-field test Results

This apparatus consists of a brown plywood arena As depicted in Fig. 1, the chronic administration of the
45 9 60 cm surrounded by wood 50 cm high walls and standard antidepressant imipramine reduced, in a signifi-
containing a frontal glass wall. The floor of the open cant manner, the immobility time of rats at 10, 20 and
field was divided into nine rectangles (15 9 20 cm each) 30 mg/kg compared with saline (F(6–58) = 3.66; P \ 0.05;
by black lines. Animals were gently placed on the left Fig. 1a). Imipramine increased the swimming time at 20
rear quadrant, and left to explore the arena for 5 min. and 30 mg/kg (F(6–64 = 9.79; P \ 0.05; Fig. 1a) and
After 12 days of treatment, rats were exposed to the imipramine also increased the climbing time at 10 and
open-field apparatus, and the number of horizontal 30 mg/kg (F(6–54) = 4.68; P \ 0.05; Fig. 1a). The intra-
(crossings) and vertical (rearings) activity performed by peritoneal treatment with harmine at the doses of 5, 10 and
each rat during the 5 min observation period was coun- 15 mg/kg also decreased significantly the immobility time
ted by an expert observer, in order to assess possible of rats compared with saline group (P \ 0.05; Fig. 1b).
effects of drug treatment on spontaneous locomotor Moreover, harmine also increased the swimming time at all
activity. doses (F(6–64) = 9.79; P \ 0.05; Fig. 1b) and increase the
climbing at 5 and 15 mg/kg (F(6–54) = 4.68; P \ 0.05;
BDNF analysis Fig. 1b). In the open-field test, the treatment with harmine
and imipramine at all doses tested did not modify the
Immediately after the forced swimming test saline, number of crossing and rearing compared with saline-
imipramine- and harmine-treated rats were killed and the treated rats (Fig. 2a, b; P [ 0.05).
skulls were removed and hippocampus was dissected and Figure 3 illustrates the effects of the chronic treatment
stored at -70°C for biochemical analysis. BDNF levels with imipramine (10, 20 and 30 mg/kg), harmine (5, 10 and
in hippocampus were measured by anti-BDNF sandwich- 15 mg/kg) and saline in BDNF protein hippocampus levels
ELISA, according to the manufacturer’s instructions of rats. A statistical significant increase in BDNF protein
(Chemicon, USA). Briefly, rat hippocampus was homo-
genized in phosphate buffer solution (PBS) with 1 mM
phenylmethylsulfonyl fluoride (PMSF) and 1 mM A 200
180 * *
(EGTA). Microtiter plates (96-well flat-bottom) were 160
Saline
* *
coated for 24 h with the samples diluted 1:2 in sample 140
Imi 10 mg/kg
Time (sec.)

Imi 20 mg/kg
diluent and standard curve ranged from 7.8 to 500 pg/ml 120 Imi 30 mg/kg
of BNDF. The plates were then washed four times with 100
sample diluent, and a monoclonal anti-BNDF rabbit 80
antibody diluted 1:1,000 in sample diluent was added to 60

each well and incubated for 3 h at room temperature. 40 * *


20
After washing, a peroxidase conjugated anti-rabbit anti-
0
body (diluted 1:1,000) was added to each well and Immobility Swimming Climbing
incubated at room temperature for 1 h. After addition of
streptavidin-enzyme, substrate and stop solution, the B 250

amount of BDNF was determined by absorbance in


200
Saline *
450 nm. The standard curve demonstrates a direct rela- Harm 5 mg/kg * * *
tionship between Optical Density (OD) and BDNF con- *
Time (sec.)

Harm 10 mg/kg
150 Harm 15 mg/kg
centration. Total protein was measured by Lowry’s
method using bovine serum albumin as a standard, as 100
previously described by Frey et al. (2006).
50 * *
Statistical analysis *
0
Immobility Swimming Climbing
All data are presented as mean ± SEM. Differences among
experimental groups in the forced swimming and open field Fig. 1 Effects of the chronic administration of imipramine (10, 20
tests and in the assessment of BDNF levels were deter- and 30 mg/kg, i.p.) (a) and harmine (5, 10 and 15 mg/kg, i.p.) (b) on
the immobility, swimming and climbing time of rats subjected to the
mined by one-way ANOVA, followed by Tukey post-hoc
forced swimming test. Bars represent means ± SEM of 15 rats.
test when ANOVA was significant; P values \0.05 were *P \ 0.05 versus saline according to ANOVA followed by Tukey
considered to be statistical significant. post-hoc test

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J. J. Fortunato et al.

A 45 immobility time of rats in the forced swimming test; (2) the


40 swimming time increases with harmine at all doses and
number of crossings

35 imipramine at 20 and 30 mg/kg; (3) the climbing time


30
increases with harmine at 5 and 15 mg/kg and imipramine at
25
20
10 and 30 mg/kg; (4) harmine and imipramine did not affect
15 spontaneous locomotor activity in the open-field test; and (5)
10 chronic treatment with harmine, but not imipramine,
5 increases BDNF protein levels in the rat hippocampus.
0
sal 10 20 30 5 10 15 In 1995, Detke et al. (1995) reported that despite the
imipramine mg/kg harmine mg/kg anti-immobility effects, antidepressant drugs that enhance
B 20 noradrenergic neurotransmission increase climbing behav-
18 iour, whereas the enhancement of serotonergic neuro-
number of rearings

16 transmission increases swimming time in the rat forced


14
swimming test. Our findings indicate that imipramine and
12
10
harmine consistently reduce immobility time and signifi-
8 cantly increase swimming and climbing time, suggesting
6 that antidepressant effects observed by imipramine and
4 harmine may be caused by serotonergic and noradrenergic
2
neurotransmission actions.
0
sal 10 20 30 5 10 15 Moreover, harmine can interact with monoamine oxi-
imipramine mg/kg harmine mg/kg dase A (MAO-A) (Kim et al. 1997) In fact, monoamine
Fig. 2 Effects of the chronic administration of harmine (5, 10 and oxidase inhibitors, which reduce the enzymatic breakdown
15 mg/kg, i.p.) and imipramine (10, 20 and 30 mg/kg, i.p.) on the of serotonin and noradrenaline, are also used to treatment
number of crossings (a) and rearings (b) of rats subjected to the open of the depression (Berton and Nestler 2006). Therefore, it
field test. Bars represent means ± SEM of 15 rats. *P \ 0.05 versus can be speculated that the antidepressant-like effects of
saline according to ANOVA followed by Tukey post-hoc test
harmine may be mediated through other mechanisms such
as interactions of harmine with serotonin receptor 2A
0,08
* (5-HT2A) (Glennon et al. 2000), imidazoline receptors (I1
0,07 *
and I2 sites) (Husbands et al. 2001), cyclindependent
0,06
BDNF pg/ug

kinases (CDK1, 2, and 5) (Song et al. 2004) and benzo-


0,05
diazepine receptor (Farzin and Mansouri 2006) which are
0,04
involved in the modulation of behavioral and molecular
0,03
actions of antidepressants.
0,02
Indeed, findings from our group have demonstrated that
0,01
a single injection of imipramine (10 and 20 mg/kg) and
0
sal 10 20 30 5 10 15 chronic administration of imipramine (10, 20 and 30 mg/
imipramine mg/kg harmine mg/kg kg) decreased the immobility time of rats in the forced
swimming test, without modifying the locomotor activity
Fig. 3 Effects of the chronic administration of harmine (5, 10 and (Garcia et al. 2008a, b). In addition, according with the
15 mg/kg, i.p.) and imipramine (10, 20 and 30 mg/k, i.p.) on the
BDNF levels in the rat hippocampus. Bars represent means ± SEM present study, our previous study also showed that chronic
of 10 rats. *P \ 0.05 versus saline according to ANOVA followed by treatment with imipramine increased swimming time at
Tukey post-hoc test doses of 20 and 30 mg/kg and increased climbing time at
doses of 10 and 30 mg/kg in rats (Garcia et al. 2008b),
levels in hippocampus was observed in rats treated with suggesting that effects exercised by imipramine on climb-
harmine only at the higher doses (10 and 15 mg/kg; ing time is dependent on dose.
F(6–64) = 3.15; P \ 0.05), but not with imipramine, com- Farzin and Mansouri (2006) demonstrated that acute
pared with saline group. treatment with harmane, norharmane and harmine dose-
dependently reduced the immobility time in the mouse
forced swimming test. Additionally, our group demon-
Discussion strated recently that acute treatment with harmine at doses
of 10 and 15 mg/kg decreased the immobility time and
The present study demonstrates that (1) chronic treatment increased the swimming and the climbing time of rats
with all doses of harmine and imipramine decreases the (Fortunato et al. 2009). This study also demonstrated that

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Chronic administration of harmine elicits antidepressant-like effects

harmine at 15 mg/kg, but not imipramine increases BDNF We revealed also that imipramine did not alter BDNF
protein levels in the rat hippocampus. Taken together, these protein levels in the hippocampus. Previous studies from
findings support rapid effects of harmine on behavioural our group also demonstrated that chronic administration of
tests used for screening antidepressant drugs. imipramine decreased the immobility time of rats in the
Additionally, another study from our group showed that forced swimming test, but did not alter BDNF protein
harmine at 15 mg/kg reversed anhedonia, the hypertrophy levels in the hippocampus (Garcia et al. 2008b). In con-
of adrenal gland weight, normalized ACTH circulating trast, Larsen et al. (2008) demonstrated a significant
levels and BDNF protein levels in rats exposed to chronic increase in BDNF mRNA expression in the granular cell
mild stress (Fortunato et al. 2010). These findings support a layer after 7 days of treatment with antidepressant venla-
rapid and robust reversion of anhedonic behaviour and faxine and after 14 days of treatment with imipramine, but
physiological alterations induced by chronic and unpre- not after 1 day of treatment. Additionally, a modest
dictable mild stress situations in rats. decreased in BDNF mRNA expression was observed in the
Our findings also showed that chronic administration of CA3 region after chronic treatment with imipramine. These
b-carboline harmine (10 and 15 mg/kg), but not imipra- results indicated that changes in BDNF levels are depen-
mine, significantly increased BDNF protein levels in the rat dent on treatment time and region of hippocampus.
hippocampus compared with saline group. Other studies Differences between imipramine and harmine in the
also showed that drugs with potential antidepressant (Li present study can be related to their dissimilar properties,
et al. 2010; Tamburella et al. 2009; Wang et al. 2010), as for example, imipramine is a tricyclic antidepressant that
well exercise (Marais et al. 2009) increase BDNF in rats inhibits norepinephrine and serotonin reuptake (Dias et al.
brain subjected to forced swimming test, which is a valid 2004), but also acts in other systems, such as, energy
behavioral despair assay widely used for screening anti- metabolism (Assis et al. 2009); in addition, imipramine
depressant drugs (McArthur and Borsini 2006). In addition, alters zinc level in the rat brain (Nowak and Schlegel-
corticostorene, which is known to increase in stress (Garcia Zawadzka 1999), and a study has showed that zinc posses
et al. 2009) decreases mobility in the forced swimming test antidepressant properties (Szewczyk et al. 2008), harmine
and BDNF levels in hippocampus (Gourley et al. 2008). act, for example with serotonin and imidazoline receptor
Alterations of hippocampal structure and function in (Glennon et al. 2000; Husbands et al. 2001).
response to stress provided the rationale for analysis of In conclusion, we showed that harmine has similar
neurotrophic factors (Duman and Monteggia 2006). Neu- behaviour effects, but different molecular effects compared
rotrophic factors are critical regulators of the formation and with imipramine. Finally, more animal studies and future
plasticity of neural networks (Huang and Reichardt 2001). double-blind, placebo-controlled studies would be neces-
Moreover, a growing body of evidence supports an sary and opportune to further confirm these observations in
important role of neurotrophic factors in mood disorders. patients with major depression and to evaluate whether
Several studies have suggested that normal BDNF-TrkB harmine could be a new option for this impairment
receptor signaling is both necessary and sufficient for disorder.
antidepressant drug action (for a review see: Castrén et al.
2007; Kozisek et al. 2008). BDNF-mediated signaling is Acknowledgments This study was supported in part by grants from
CNPq-Brazil (JQ, FK, JAC, AWZ, and JEH), FAPESP-Brazil (JAC,
involved in neuroplastic responses to stress and antide- AWZ, and JEH), FAPESC-Brazil (JQ), Instituto Cérebro e Mente-
pressants (Krishnan and Nestler 2008). In fact, reduced Brazil (JQ and FK) and UNESC-Brazil (JQ). JQ, FK, JAC and AWZ
serum BDNF levels might to be correlated to depression are recipients of CNPq (Brazil) Productivity fellowships. GZR is
(Karege et al. 2002), whereas increases in brain BDNF holder of a FAPESC/CAPES studentship. This study was also spon-
sored by THC-Pharm (Frankfurt, Germany) and STI-Pharm (UK)
levels is suggested to produce an antidepressant action who kindly provided harmine.
(Shirayama et al. 2002; Siuciak et al. 1997). Furthermore,
analysis of postmortem hippocampus demonstrates that the
expression of BDNF is decreased in depressed patients
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