Effects of sodium butyrate in animal models of mania anddepression: implications as a new mood stabilizerWilson R. Resendea, Samira S. Valvassoria, Gislaine Z. Reusa,Roger B. Varelaa, Camila O. Arenta, Karine F. Ribeiroa, Daniela V. Bavarescoa,Monica L. Andersenb, Alexandra I. Zugnoa and Joao Quevedoa

Bipolar disorder is a severe mood disorder with high

morbidity and mortality. Despite adequate treatment,

patients continue to have recurrent mood episodes, residual

symptoms, and functional impairment. Some preclinical

studies have shown that histone deacetylase inhibitors may

act on depressive-like and manic-like behaviors. Therefore,

the aim of the present study was to evaluate the effects of

sodium butyrate (SB) on behavioral changes in animal

models of depression and mania. The animals were

submitted to protocols of chronic mild stress or maternal

deprivation for induction of depressive-like behaviors and

subjected to amphetamine, or ouabain administration

for induction of manic-like behaviors. SB reversed

the depressive-like and manic-like behaviors

evaluated in the animal models. From these results

we can suggest that SB may be a potential mood

stabilizer. Behavioural Pharmacology 24:569–579 �c 2013

Wolters Kluwer Health | Lippincott Williams & Wilkins.

Behavioural Pharmacology 2013, 24:569–579

Keywords: animal model, bipolar disorder, depression, mania, rat,sodium butyrate

aLaboratory of Neurosciences, National Institute for Translational Medicine(INCT-TM), and Center of Excellence in Applied Neurosciences of Santa Catarina(NENASC), Graduate Program in Health Sciences, Health Sciences Unit,University of Southern Santa Catarina, Criciuma, Santa Catarina andbDepartment of Psychobiology, University Federal of Sao Paulo,Sao Paulo, Brazil

Correspondence to Samira S. Valvassori, PhD, Laboratory of Neurosciences,Graduate Program in Health Sciences, Health Sciences Unit, University ofSouthern Santa Catarina, Criciuma, SC 88806-000, BrazilE-mail: samiravalvassori@unesc.net

Received 27 January 2013 Accepted as revised 2 July 2013

IntroductionBipolar disorder (BD) is a severe mood disorder with high

morbidity and a high likelihood of recurrence. It is

characterized by recurrent episodes of mania followed by

depression (Muller-Oerlinghausen et al., 2002). Although

the clinical hallmark for the diagnosis of BD is the

presence of manic symptoms, depression represents the

predominant mood state for treated patients with bipolar

I and II disorders (Judd et al., 2003; Kupka et al., 2007).

Currently approved treatments for BD include lithium

(Li), valproate (VPA), and antipsychotics. However, many

bipolar patients do not respond adequately to these

medications, and continue to have recurrent mood

episodes, residual symptoms, functional impairment,

psychosocial disability, and significant medical and

psychiatric comorbidity (Zarate et al., 2006).

Increasingly, it has been described in the literature that

histone deacetylases (HDAC) may be a promising target

for the treatment of several neurological disorders (Graff

and Tsai, 2013). HDAC inhibitors (HDACi) increase

histone acetylation, which diminishes the affinity be-

tween histone proteins and DNA, and thus facilitates

genomic transcription (Brownell and Allis, 1996; Shahba-

zian and Grunstein, 2007). VPA, an anticonvulsant and

mood-stabilizing drug, has been characterized as an

HDACi (Gottlicher et al., 2001). Several studies have

shown that VPA has neuroprotective effects, suggesting

that the therapeutic mechanisms of this drug involve, at

least in part, HDAC inhibition (Dou et al., 2003; Chen

et al., 2006; Leng et al., 2008).

It was recently demonstrated that microinjection of

sodium butyrate (SB) and VPA, two HDACi, into the

ventricle, amygdala, striatum, or prefrontal cortex blocked

the hyperactivity induced by methamphetamine (Arent

et al., 2011). In addition, it was also demonstrated that

intraperitoneal (i.p.) SB and VPA administration reversed

and prevented D-amphetamine (D-AMPH)-related manic

behavior. In addition, SB protected against D-AMPH-

induced mitochondrial complex damage in the brains of

rats (Moretti et al., 2011). Schroeder et al. (2007) showed

that cotreatment with SB and fluoxetine resulted in a

significant decrease of immobility scores in the tail

suspension test, a screening test for antidepressant-like

drugs, both acutely and chronically, suggesting that SB

exerts antidepressant-like effects in the mouse. It was

also observed that repeated administration of SB

significantly reduced immobility in the forced swimming

test (FST) (Yamawaki et al., 2012), reinforcing the

evidence for the antidepressant-like effects of SB. Taking

into account the studies cited above, we suggest that SB

might be a potential new mood stabilizer, because it

seems to act in both mania and depression.

The FST and tail suspension test are well-established

screening tools for antidepressant efficacy, with robust

predictive validity (Porsolt et al., 1977; Steru et al., 1985;

Research report 569

0955-8810 �c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FBP.0b013e32836546fc

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Nestler and Hyman, 2010). Nevertheless, the effects of SB

in rats subjected to different types of stressors remain

unknown. Exposure to chronic mild stress (CMS) induces

depressive-like behaviors in rats, such as decreased intake of

sweet food (a measure of anhedonia) and an increase in

immobility in the FST. The reversion of these effects by

chronic antidepressant treatment makes CMS one of

the most valid models of depression (Willner, 2005). The

maternal deprivation (MD) paradigm is an animal model

that has been used to study the long-term effects of child

abuse and neglect. Experiments showed that rats subjected

to trauma and stress early in life display depressive behaviors

when adult, results that mimic clinical conditions. It is

apparent that adverse events early in life may affect the

development and maturation of the brain (Vazquez et al.,2005).

Besides manic-like effects induced by psychostimulants,

ouabain-induced hyperlocomotion in rats has been

considered a good animal model of mania and has been

widely used to screen new mood-stabilizing drugs

(Brocardo et al., 2010; Gao et al., 2011; Yu et al., 2011).

Ouabain is a potent inhibitor of the sodium pump

(sodium-activated and potassium-activated adenosine

triphosphatase or Na + K + -ATPase). The literature

suggests that a small decrease in sodium pump activity

may result in neuronal hyperexcitability, giving rise to

manic symptoms, such as hyperactivity (El-Mallakh,

1983). Evaluation of the effects of SB in the model of

mania induced by ouabain is important to assess the

effects of this drug on other cellular mechanisms, which

are also seen in BD.

In light of these findings, we designed the present study

to investigate the effects of SB administration in rats

subjected to animal models of depression induced by

CMS and MD, and mania induced by D-AMPH and

ouabain.

MethodsSubjects

Male adult Wistar rats (60 days old) were obtained from

the breeding colon (University of Southern Santa

Catarina, Criciuma, SC, Brazil). The animals were housed

five to a cage, on a 12-h light/dark cycle (lights on at

07:00 h), with free access to food and water. All

experimental procedures were carried out in accordance

with the National Institutes of Health Guide for the Care

and Use of Laboratory Animals and the guidelines of the

Brazilian Society for Neuroscience and Behavior. The

study was approved by the local ethics committee

(Comite de Etica no Uso de Animais da Universidade

do Extremo Sul Catarinense), and all efforts were made

to minimize animal suffering, to reduce the number of

animals used, and to utilize alternatives to in-vivo

techniques.

Experimental protocols

Acute treatment protocol

Different groups of rats (n = 15 each) received a single i.p.

injection of SB (500 mg/kg), imipramine (IMI; 10 mg/kg),

or saline (Sal; NaCl 0.09%). The dose of SB used was

based on our previous study (Moretti et al., 2011). Rats

were tested in the open field and FST 1 h after IMI, SB,

or Sal administration (Fig. 1a). Different animals were

used for each test.

Subchronic treatment protocol

In this experimental protocol, different groups of rats

(n = 10/group) received i.p. injections of SB (500 mg/kg),

IMI (10 mg/kg), or Sal (NaCl 0.09%) twice daily for 7

days. The range of doses of SB used was chosen on the

basis of our previous study (Moretti et al., 2011). Rats

were tested in the open field and FST 1 h after the last

IMI, SB, or Sal administration (Fig. 1b). Different animals

were used for each test.

Chronic mild stress protocol

The CMS protocol was adapted from the procedure

described by Gamaro et al. (2003). CMS was applied for

40 days, using the following stressors: (i) 24-h food

deprivation; (ii) 24-h water deprivation; (iii) 1–3 h of

restraint as described later, (iv) 1.5–2 h of restraint at

41C; (v) forced swimming for 10 or 15 min as described

later; (vi) flashing light for 120–210 min; (vii) isolation

(2–3 days). Stressors were applied at different times

every day, to minimize their predictability. Restraint was

carried out by placing the animal in a 25� 7 cm plastic

tube and adjusting it with plaster tape on the outside,

thus not allowing the animal to move. There was a 1 cm

hole at the end of the tube for breathing. Forced

swimming was carried out by placing the animal in a

glass tank measuring 50� 47 cm with 30 cm of water at

23±21C. Exposure to flashing light was done by placing

the animal in a 60� 60� 25 cm plywood box divided into

16 cells of 15� 15� 25 cm with a frontal glass wall. A

40 W lamp flashing at a frequency of 60 flashes/min was

used.

Six groups of animals were used (n = 10/group): control

or CMS, treated with SB (500 mg/kg), IMI (10 mg/kg), or

Sal (NaCl 0.09%), which were injected i.p. twice a day for

7 days, after the CMS procedure. The animals were

subjected to the FST or open-field test, as described

below, 1 h after the last drug administration. Anhedonia

tests (see below) were conducted, over 7 days, 1 h after

drug administration (Fig. 1c). Different animals were

used for each test.

Maternal deprivation protocol

Pregnant female Wistar rats were maintained in individual

cages until the delivery day. MD was carried out for

570 Behavioural Pharmacology 2013, Vol 24 No 7

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180 min a day from PND-01 to PND-10, as described in

previous studies (Mello et al., 2009). The mother was

removed from the home cage and taken to another room.

Pups were maintained in their home cages (grouped in

the nest in the presence of maternal odor). At the end of

each daily deprivation session, the mothers were returned

to their home cages; this procedure was carried out during

the light part of the cycle, between 08:00 and 14:00 h.

Control rats remained in their home cages together with

their mothers throughout. Only after PND-11 were the

cages cleaned normally again, according to the standard

laboratory routine. On PND-21 the animals were weaned,

and the males were maintained in groups of four, in

50� 25� 40 cm plastic cages with a stainless-steel lid,

with free access to food and water, as for all the other

animals in our animal housing facility.

SB (500 mg/kg), IMI (10 mg/kg), or Sal (NaCl 0.09%)

were injected i.p. twice a day, over 7 days, after the

animals had reached the age of 3 months. The animals

were randomly divided into MD and control groups

before the start of treatment, each of which was further

subdivided into SB, IMI, and Sal subgroups (n = 10). The

animals were subjected to the FST and open-field test, as

described below, 1 h after the last drug administration

(Fig. 1d). Different animals were used for each test.

Animal model of mania induced by D-amphetamine

In this protocol, we modeled an acute manic episode

according to the method of Frey et al. (2006a). The

animals received daily i.p. injections of D-AMPH (Sigma-

Aldrich, St Louis, Missouri, USA) (2 mg/kg) or Sal for 14

days. On the 8th day of treatment, the Sal and D-AMPH

groups were divided into four subgroups (n = 10) and

treated with (a) SB (500 mg/kg i.p.), (b) Li (47.5 mg/kg

i.p.), (c) VPA (200 mg/kg i.p.), or (d) Sal, twice daily for 7

days. On the 15th day of treatment, the animals received a

single injection of D-AMPH or Sal, and locomotor activity,

in the open-field test, was assessed 2 h later (Fig. 1e).

Animal model of mania induced by ouabain

Animals were anesthetized by i.p. injection of ketamine

(80 mg/kg) and xylasine (10 mg/kg), and a 27 G 9 mm

guide cannula was implanted stereotaxically at 0.9 mm

posterior to the bregma, 1.5 mm right from the midline,

and 1.0 mm above the lateral ventricle, and fixed with

acrylic cement. Animals were allowed 3 days to recover

from surgery. Postmortem verification of cannula place-

ments was performed as previously described (Barros

et al., 1999). Brains were verified by histological examina-

tion, in 33% of animals in each group. All of these

cannulae were correctly placed.

Fig. 1

IMI/SB/ Sal

IMI/SB/ Sal

IMI/SB/ SalIMI/SB/ SalCMS/non-CMS

D-AMPH/Sal

Day

D-AMPH/Sal +Li/VPA/SB/Sal

D-AMPH/Sal

MD/non-MD

Day 1st

Day1st 40th

1st 8th 14th 15th

10thPND 1st 60th 61th 62th

4th9th 10th

63th 64th 65th 67th41th 42th 43th 44th 45th 46th

47th

6th 7th0

FST (training)FST (training)

Training (SFC) Training (SFC)Test (SFC) Test (SFC)

FST (training)FST (training)

Locomotor activity/FST (test)Locomotor activity/FST (test)

Locomotor activity

Locomotor activity

Surgery OUA/ aCSF

Day 0

Recovery Sal/Li/SB/VPA

Locomotor activity/FST

(test)

Locomotor activity/FST

(test)

24 h 25 h

(a) (b)

(c) (d)

(e) (f)

Schematic illustration of experimental protocols. (a) Acute treatment protocol. (b) Subchronic treatment protocol. (c) Chronic mild stress (CMS)protocol. (d) Maternal deprivation (MD) protocol. (e) Animal model of mania induced by D-amphetamine (D-AMPH). (f) Animal model of mania inducedby ouabain (OUA). aCSF, artificial cerebrospinal fluid; FST, forced swimming test, IMI, imipramine; Li, lithium; Sal, saline; SB, sodium butyrate; SFC,sweet food consumption; VPA, valproate.

Sodium butyrate as a new mood stabilizer Resende et al. 571

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We designed this experiment to model the management

of an acute manic episode. Animals (n = 72) received a

single intracerebroventricular injection of 5 ml of ouabain

10 – 3 mol/l dissolved in artificial cerebrospinal fluid

(aCSF), or 5 ml of aCSF alone, on the 4th day after

surgery (El-Mallakh et al., 2003; Riegel et al., 2009). A

30 G cannula was placed into the guide cannula and

connected by a polyethylene tube to a microsyringe. The

tip of the cannula infusion protruded 1.0 mm beyond

the cannula guide, aiming at the right lateral brain

ventricle. From the day after the injection of ouabain or

aCSF, the rats were treated twice daily for 6 days with i.p.

injections of Li (47.5 mg/kg), VPA (200 mg/kg), or SB

(500 mg/kg). Locomotor activity in the open-field test

was measured 7 days after ouabain administration, the

day following the final drug treatment (Fig. 1f).

Behavioral tests

Forced swimming test

The FST was conducted according to previous reports

(Porsolt et al., 1977; Detke et al., 1995). The test involved

two individual exposures to a cylindrical tank containing

water in which rats could not touch the bottom of the

tank or escape. The tank was made of transparent

Plexiglas, 80 cm tall, 30 cm in diameter, and was filled

with water (22–231C) to a depth of 40 cm. Water in the

tank was changed after each rat. For the first exposure,

rats were placed in the water for 15 min (pretest session).

Twenty-four hours later, rats were placed in the water

again for a 5 min test session and the time spent in the

following behaviors was recorded: immobility (i.e. no

additional activity was observed other than that required

to keep the rat’s head above the water), climbing, which

was defined as upward-directed movements of the

forepaws along the side of the swim chamber, and

swimming (i.e. movement usually horizontal throughout

the swim chamber).

Open-field test

This apparatus consisted of a brown plywood arena

45� 60 cm surrounded by wooden walls 50 cm high

and containing a frontal glass wall. The floor of the open

field was divided by black lines into nine rectangles

(15� 20 cm each). Animals were gently placed on the left

rear quadrant, and left to explore the arena for 5 min. The

numbers of horizontal (crossings) and vertical (rearings)

activities performed by each rat were counted. The open-

field arena was covered with a plastic adhesive, and

cleaned with 10% alcohol between rats.

Sweet food consumption (anhedonia test)

The consumption of sweet food was used as a measure of

anhedonia. This test was performed between 08:00 and

12:00 h. Animals were placed in a rectangular wooden box

(40� 15� 20 cm), which was placed in an illuminated

room (150 lx in the center of the box). Ten Froot Loops

(Kellogg’s pellets of wheat and corn starch and sucrose;

Kellogg’s Company, Battle Creek, Michigan, USA) were

placed in the center of the box. Animals were submitted to

five 3-min sessions, once a day, to familiarize with this food

(training sessions). Afterwards, animals were exposed to

two 3-min test sessions, and the number of ingested pellets

was measured (Gamaro et al., 2003). When the animal ate

part of a Froot Loops (e.g. 1/3 or 1/4), this fraction was

considered as one unit. In addition, in the two test sessions,

but not in the training sessions, sweet food consumption

was measured without food deprivation. This was done as

food deprivation, which is used in many behavior tasks as a

motivating stimulus, and may also be an acute stressor

(Katz, 1981; Gamaro et al., 2003). The amount of Froot

Loops consumed was expressed as the average of the two

test sessions. After testing, the apparatus was cleaned, to

avoid the smell of previous rats affecting the behavior of

subsequent animals.

Drugs

SB was purchased from Sigma-Aldrich and IMI from

Novartis Pharmaceutical Industry (Basel, Switzerland).

IMI and SB were dissolved in Sal immediately before use.

All treatments were administered by i.p. injection in a

volume of 1 ml/kg.

Statistical analysis

Data are presented as mean±SEM. The variables were

analyzed according to their distribution through the

Shapiro–Wilk test for normality. The homogeneity of

variances among groups was assessed by the Levene test.

Differences among experimental groups were determined

by one-way or two-way analysis of variance (ANOVA),

followed by Tukey’s post-hoc test. A value of P less than

0.05 was considered to be significant.

ResultsOne-way ANOVA showed that a single injection of IMI

or SB produced antidepressant-like effects in the FST

[immobility: F(2,67) = 323.38, P < 0.001; climbing:

F(2,67) = 243.9, P < 0.001; swimming: F(2,67) = 59.13,

P < 0.001]. Post-hoc analysis indicated that IMI and SB

produced a significant reduction of immobility and an

increase of climbing in the FST. The acute administration

of SB also increased swimming time (Fig. 2a). In addition,

there was no difference in open-field activity, tested at

the same time point as the FST, indicating that the

effects of IMI and SB, in the FST, were not due to

increases in locomotor activity (Fig. 2b).

We next evaluated whether the antidepressants effects of

SB continue after subchronic administration (Fig. 2c).

One-way ANOVA revealed that subchronic, 7-day treatment

with IMI or SB produced antidepressant effects in the

FST [immobility: F(2,40) = 311.69, P < 0.001; climbing:

F(2,40) = 54.67, P < 0.001; swimming: F(2,40) = 30.33,

P < 0.001]. Post-hoc analysis indicated that IMI and SB

572 Behavioural Pharmacology 2013, Vol 24 No 7

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produced a significant reduction of immobility and an

increase of climbing and swimming in the FST. Moreover,

there was no difference in open-field activity, tested at the

same time point as the FST (Fig. 2d).

Chronic mild stress

As can be seen in Fig. 3a, CMS-exposed rats, when

compared with unstressed control rats, exhibited a

reduction in sweet food consumption. In addition, CMS

exposure increased immobility and decreased swimming

time in the FST (Fig. 3b). The subchronic administration

of IMI or SB reversed the CMS-induced behavioral

deficit in both the sweet food consumption test and the

FST. Administration of IMI or SB did not affect sweet

consumption in nonstressed control rats. However, in the

FST IMI or SB administration decreased immobility and

increased climbing in nonstressed rats. As a control, IMI

or SB treatment had no effect on locomotor activities

tested at the same time point as FST, indicating that the

reduction of immobility observed in the FST after IMI or

SB treatments was not due to locomotor changes

(Fig. 3c). Analysis by two-way ANOVA showed significant

main effects of CMS exposure [sweet food consumption:

F(1,84) = 71.64, P < 0.001; immobility: F(1,74) = 428.73,

P < 0.001; climbing: F(1,74) = 2.71, NS; swimming:

F(1,74) = 109.76, P < 0.001] and treatment [sweet food

consumption: F(2,64) = 40.72, P < 0.001; immobility:

F(2,74) = 287.83, P < 0.001; climbing: F(2,74) = 312.74,

P < 0.001; swimming: F(2,74) = 48.43, P < 0.001], and a

significant CMS exposure� treatment interaction [sweet

food consumption: F(2,64) = 44.53, P < 0.001; immobility:

F(2,74) = 83.94, P < 0.001; climbing: F(2,74) = 1,62, NS;

swimming: F(2,74) = 30.93, P < 0.001].

Maternal deprivation

The rats in the MD group had significant increased

immobility and decreased swimming time in the FST,

compared with the rats in the maternal care group

(control + Sal), (Fig. 4a). IMI or SB administration

significantly decreased the immobility time of the rats

in the MD group, to the level of the maternal care group.

IMI or SB administration decreased immobility in rats of

the maternal care group. In addition, IMI and SB

increased climbing in rats of both the maternal care and

MD groups, but IMI was more potent than SB. In

contrast, only SB increased swimming time in rats of the

Fig. 2

300

200

100

0

300

200

100

0Forc

ed s

wim

min

g te

st (s

)Fo

rced

sw

imm

ing

test

(s)

Immobility

∗ ∗∗ ∗#

∗#

∗#

Climbing Swimming

Immobility

∗ ∗ ∗

∗

∗#

Climbing Swimming

Crossings Rearings

Crossings Rearings

SBAcute treatmentIMI

Sal

SBAcute treatmentIMI

Sal

50

40

30

20

Loco

mot

or a

ctiv

ity

10

0

50

40

30

20Lo

com

otor

act

ivity

10

0

SBChronic treatmentIMI

SalChronic treatment

SBIMISal

(a) (b)

(c) (d)

Effects of acute (a, b) and chronic (c, d) saline (Sal), imipramine (IMI), or sodium butyrate (SB) treatment in the forced swimming test and open-fieldtest. Results are expressed as mean±SEM. Differences among experimental groups were determined by one-way ANOVA followed by Tukey’s post-hoc test. *P < 0.001 as compared with saline-treated controls. #P < 0.001, IMI as compared with SB. ANOVA, analysis of variance.

Sodium butyrate as a new mood stabilizer Resende et al. 573

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maternal care group; both IMI and SB increased the

swimming time of the rats in the MD group, but only

the effect of SB reached the level of the maternal care

group. Neither IMI nor SB treatment had any effect on

locomotor activities tested at the same time point as the

FST, indicating that the reduction of immobility observed

in the FST after IMI or SB treatments was

not due to locomotor changes (Fig. 4b). Analysis by

two-way ANOVA showed significant main effects of

MD [immobility: F(1,54) = 404.15, P < 0.001; climbing:

F(1,54) = 1.03, NS; swimming: F(1,54) = 319.9, P <

0.001] and treatment [immobility: F(2,54) = 322.58,

P < 0.001; climbing: F(2,54) = 290.56, P < 0.001; swim-

ming: F(2,54) = 144.61, P < 0.001], and significant MD

� treatment interaction [immobility: F(2,54) = 100.84,

P < 0.001; climbing: F(2,54) = 2.7, P < 0.01; swimming:

F(2,54) = 73.82, P < 0.001].

D-AMPH (Fig. 5a) shows the influence of mood

stabilizers on the manic-like behavior elicited by

D-AMPH administration, which replicated previous data

from our group (Frey et al., 2006a; Moretti et al., 2011). For

locomotion (crossings), the two-way ANOVA revealed

significant main effects of D-AMPH administration

[F(1,56) = 78.02, P < 0.001] and treatment [F(3,56)

= 36.63, P < 0.001], and a significant D-AMPH adminis-

tration� treatment interaction [F = (3,56) = 44.96, P <

0.001]. For exploration (rears), the two-way ANOVA also

revealed significant main effects of D-AMPH administra-

tion [F(1,56) = 31.95, P < 0.001] and treatment [F(3,56) =

24.98, P < 0.001], and a significant D-AMPH administration

� treatment interaction [F(3,56) = 30.48, P < 0.001].

Further analysis with Tukey’s post-hoc test showed that

the administration of D-AMPH increased locomotion in rats,

and this effect was reversed and prevented by Li, VPA, and

SB. Li, VPA, and SB alone did not alter behavioral measures,

Fig. 3

6

4

Sw

eet f

ood

cons

umpt

ion

2

0Sal

300

200

∗ ∗# # ∗ ∗ ∗ ∗

∗

∗

∗

∗ #

#

# #

100

0

50

40

30

Loco

mot

or a

ctiv

ity

20

10

0Crossings Rearings

Control+SalControl+IMI

Control+SBCMS+Sal

CMS+IMICMS+SB

Immobility

Forc

ed s

wim

min

g te

st (s

)

Climbing Swimming

IMI

Control CMS

SB Sal IMI SB

(a)

(b)

(c)

Effects of saline (Sal), imipramine (IMI), or sodium butyrate (SB)treatments on sweet food consumption (a), forced swimming test (b),and open-field test (c) in rats submitted to the chronic mild stress(CMS) protocol. Results are expressed as mean±SEM. Differencesamong experimental groups were determined by two-way ANOVAfollowed by Tukey’s post-hoc test. *P < 0.001 as compared with saline-treated controls. #P < 0.001 as compared with the CMS + Sal group.ANOVA, analysis of variance.

Fig. 4

300

∗

∗∗

∗

∗

∗

∗

∗#

#

∗

# #

200

Forc

ed s

wim

min

g te

st (s

)Lo

com

otor

act

ivity

100

0Immobility Climbing Swimming

60

40

20

0Crossings Rearings

Control+SalControl+IMI

Control+SBMD+Sal

MD+IMIMD+SB

(a)

(b)

Effects of saline (Sal), imipramine (IMI), or sodium butyrate (SB)treatments in the forced swimming (a) and open-field (b) tests in ratssubmitted to the maternal deprivation (MD) protocol. Results areexpressed as mean±SEM. Differences among experimental groupswere determined by two-way ANOVA followed by Tukey’s post-hoctest. *P < 0.001 as compared with saline-treated controls. #P < 0.001as compared with the MD + Sal group. ANOVA, analysis of variance.

574 Behavioural Pharmacology 2013, Vol 24 No 7

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indicating that the effects of drugs on D-AMPH-treated rats

were not associated with sedation.

Ouabain

Figure 5b shows the influence of treatment with Li and

VPA on the manic-like behavior elicited by intracerebro-

ventricular ouabain administration. For locomotion (cross-

ings), the two-way ANOVA revealed significant main

effects of ouabain administration [F(1,56) = 62.28,

P < 0.001] and treatment [F(3,56) = 24.49, P < 0.001],

and a significant ouabain administration� treatment

interaction [F(3,56) = 20.45, P < 0.001]. For exploration

(rears), the two-way ANOVA also revealed significant

main effects of ouabain administration [F(1,56) = 25.35,

P < 0.001] and treatment [F(3,56) = 16.86, P < 0.001],

and a significant ouabain administration� treatment

interaction [F(3,56) = 12.41, P < 0.001]. Further analysis

with Tukey’s post-hoc test showed that administration of

ouabain increased locomotion and exploration in rats, and

these effects were reversed and prevented by Li, VPA,

and SB. Li, VPA, or SB alone did not alter behavioral

measures, indicating that the drug effects on ouabain-

treated rats were not associated with sedation.

DiscussionThe current study provides further evidence that a

HDAC inhibitor, SB, produces antidepressant-like and

antimanic-like effects in preclinical animal models of

depression and mania, respectively.

FST is the most commonly used screening test for

antidepressant activity (Porsolt et al., 1978). The results

of the present study demonstrate that both a single and

subchronic (twice daily for 7 days) administration of SB

induced antidepressant-like effects in the FST. In line

with our results, it was recently reported that repeated

administration of SB and IMI significantly reduced

immobility in the FST and tail suspension test (Yamawaki

et al., 2012), also suggesting an antidepressant-like effect of

SB. In addition, Gundersen and Blendy (2009) have

reported that the administration of SB, at 100 mg/kg

acutely (three injections over 24 h), increased immobility

in the FST and increases latency to consume food in a

novel environment, in the novelty-induced hypophagia

paradigm, an anxiogenic effect. In contrast, in the same

study, it was reported that chronic (twice daily for 21 days)

treatment with SB had no effect on latency to consume in

the novelty-induced hypophagia or immobility in the FST.

These studies suggest that the effects of SB depend on

the dose and duration of drug administration.

CMS exposure induces depressive-like behaviors in rats,

such as anhedonia and an increase of immobility in the FST.

The reversal of these effects by chronic antidepressant

treatment makes CMS one of the most valid models of

Fig. 5

100(a)

(b)

80

60

40

20

0Crossings

Loco

mot

or a

ctiv

ity

100∗

# # #∗

# # #

∗

# # # ∗

# # #

80

60

40

20

0

Loco

mot

or a

ctiv

ity

Rearings

Crossings Rearings

Sal+SalSal+LiSal+VPASal+SBD-AMPH+SalD-AMPH+LiD-AMPH+VPAD-AMPH+SB

aCSF + SalaCSF + LiaCSF + VPAaCSF + SBOUA + SalOUA + LiOUA + VPAOUA + SB

Effects of saline (Sal), lithium (Li), valproate (VPA), or sodium butyrate (SB) treatments in the open-field test in rats submitted to the animal model ofmania induced by D-AMPH (a) or by OUA (b). Results are expressed as mean±SEM. Differences among experimental groups were determined bytwo-way ANOVA followed by Tukey’s post-hoc test. *P < 0.001 as compared with the Sal + Sal or aCSF + Sal groups. #P < 0.001 as compared withthe D-AMPH + Sal or OUA + Sal groups. aCSF, artificial cerebrospinal fluid; D-AMPH, D-amphetamine; ANOVA, analysis of variance; OUA, ouabain.

Sodium butyrate as a new mood stabilizer Resende et al. 575

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

depression (Willner, 2005). In the present study, CMS-

exposed rats, when compared with unstressed controls,

exhibited a reduction in sweet food consumption, an

indication of anhedonia. In addition, CMS exposure

increased immobility in the FST. Subchronic SB and IMI

treatment reversed the CMS-induced behavioral deficits in

both the sweet food consumption test and the FST. It is

important to emphasize that previous exposure to forced

swimming as a stressor, in the CMS rats, might create an

artificial difference between the nonstressed and stressed

groups, as stressed animals are habituated to the FST

(Petit-Demouliere et al., 2005).

It has been reported that CMS significantly decreased

the acetylation of histone 3 (H3) and histone 4 (H4) in

the CA3 region and dentate gyrus of hippocampus of

animals compared with control animals. In addition, the

application of HDAC inhibitors (SB and sirtinol) to

hippocampal slices from control and CMS animals

revealed increased histone acetylation in CMS animals,

suggesting that changes in histone acetylation in the

hippocampus may contribute to stress-induced pathology

(Ferland and Schrader, 2011).

The MD paradigm is an animal model that has been used

to study the long-term effects of child abuse and neglect.

Experiments showed that rats subjected to trauma and

stress early in life display depressive-like behaviors when

adult, results that mimic clinical conditions. It is apparent

that adverse events early in life may affect the develop-

ment and maturation of the brain (Vazquez et al., 2005).

In this study, the immobility time during the FST was

increased following MD, indicating that MD induced a

depressive-like behavior in the rats. Immobility time was

significantly decreased by SB and IMI, suggesting that

SB reverses this depressive-like behavior of maternal-

separated rats. In an important epigenetic study, it was

demonstrated that the increase of maternal care by rat

mothers altered the epigenome of the offspring at a

glucocorticoid receptor gene promoter in the hippocam-

pus. The offspring of mothers that showed high levels of

maternal care were found to have differences in DNA

methylation, as compared with offspring with low

maternal care. Central infusion of trichostatin A, a HDAC

inhibitor, removed the differences in histone acetylation,

DNA methylation, glucocorticoid receptor expression,

and hypothalamic–pituitary–adrenal responses to stress,

suggesting a relationship among the epigenomic state,

glucocorticoid receptor expression, and the maternal

effect on stress responses in the offspring (Weaver et al.,2004). Considering that adverse events early in life may

affect the development and maturation of the brain

(Vazquez et al., 2005), inducing behavior alterations, as

observed in the present study, we propose that SB may

promote neuronal development and maturation.

Histone acetylation has a central role in transcriptional

activation, whereas deacetylation of histones correlates

with the transcriptional repression and silencing of genes.

Genetic repression may have an important role in neuronal

atrophy and degenerative diseases (Salminen et al., 1998).

Preclinical and clinical studies demonstrate that changes in

levels of various genes in the brain, including the BDNFgene, play a role in the pathophysiology of depression. The

regulation of neurotrophic factor expression and signaling

by antidepressant treatment, together with evidence of

stress-induced cell atrophy and loss, suggest a neurotrophic

hypothesis of depression (Banasr and Duman, 2007;

Schmidt and Duman, 2007; Koo and Duman, 2009; Krish-

nan and Nestler, 2010). It is well described in the literature

that antidepressants increase adult neurogenesis in

the hippocampus, as well as gliogenesis in the brain

(Duman and Monteggia, 2006; Banasr and Duman, 2007).

Studies have demonstrated that BDNF signaling is

necessary and sufficient for the actions of antidepressants

in animal models of depression (Duman and Monteggia,

2006; Castren et al., 2007).

Wu et al. (2008) have demonstrated that the HDAC

inhibitors SB and trichostatin A upregulate GDNF and

BDNF expression in astrocytes and protect DA neurons. In

a previous study, the HDAC inhibitors trichostatin A, SB,

and VPA enhanced serotonin-stimulated BDNF geneexpression in the glioma cells (Morita et al., 2009). Glial

cell differentiation was suggested to be closely associated

with the protection of neuronal cells, which may be

because of the enhancement of their abilities to produce

BDNF in response to serotonin stimulation (Morita and

Her, 2008). SB treatment also increased the number of

cells expressing polysialic acid-neural cell adhesion mole-

cule, nestin, glial fibrillary acidic protein, phospho-cAMP

response element-binding protein (CREB), and BDNF in

various brain regions after cerebral ischemia, which may

contribute to the beneficial effects of SB (Kim et al., 2009).

The behavioral effects of stimulants, such as D-AMPH,

have been widely used as an animal model of mania,

because D-AMPH induces psychomotor agitation, which is

commonly observed during mania, and locomotor activity

is easily measured in rats (Davies et al., 1974; Berggren

et al., 1978; Gould et al., 2001). Studies have suggested

that alteration in the dopaminergic system is a predomi-

nant etiological factor for BD (Frey et al., 2006b; Berk et al.,2007; Valvassori et al., 2010). We replicated here previous

data from our group. Administration of D-AMPH increased

locomotion and exploration in rats, and this effect was

reversed by SB, VPA, and Li, indicating antimanic-like

effects of SB (Moretti et al., 2011). In a previous study, it

was found that the microinjection of SB and VPA into the

ventricle, amygdala, striatum, or prefrontal cortex, but not

hippocampus, blocked the hyperactivity induced by

methamphetamine (Arent et al., 2011). In a rat model of

cocaine-induced conditioned place preference, SB treat-

ment facilitated extinction of drug-seeking behavior

(Malvaez et al., 2010). Data from preclinical studies

576 Behavioural Pharmacology 2013, Vol 24 No 7

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

indicate that HDAC inhibitors upregulate GDNF and

BDNF expression in astrocytes, and protect DA neurons

through HDAC inhibition. In the same study, the authors

showed that astrocytes may be a critical neuroprotective

mechanism of HDAC inhibitors, revealing a novel target

for the treatment of psychiatric and neurodegenerative

diseases (Wu et al., 2008).

The Na + /K + -ATPase inhibitor, ouabain, induces hyper-

activity in the open field, and has also been proposed as a

model of BD mania (El-Mallakh et al., 1995; Jornada et al.,2010). Several studies have reported Na + /K + -ATPase

alterations in BD patients (El-Mallakh and Wyatt,

1995; Huff et al., 2010; Banerjee et al., 2012), which may

be explained, at least partially, by mitochondrial dysfunc-

tion (Murashita et al., 2000; Kato and Kato, 2000; Kato

et al., 2001). In the present study, we demonstrated that

SB reversed the hyperactivity induced by D-AMPH, Li,

and VPA, indicating an antimanic-like effect of SB. In a

previous study, it was found that the tubacin, a specific

HDAC6 inhibitor, dramatically enhanced mitochondrial

movement in hippocampal neurons, suggesting that

HDAC6 plays an important role in the modulation of

mitochondrial transport (Chen et al., 2010). In this

context, SB also was able to reverse and prevent the

decrease in activity of mitochondrial respiratory-chain

complexes induced by D-AMPH (Moretti et al., 2011).

Knowing that the Na + /K + -ATPase is ATP dependent,

we can suggest that administration of SB may improve

mitochondrial activity, restoring Na + /K + -ATPase func-

tion in the ouabain-injected rats.

In a study to screen for potential mood stabilizer drugs, it

was found that SB exhibited an inositol-depleting effect,

which was achieved without significant adverse effect on

cell growth, pointing to lesser toxicity compared with

VPA (Azab et al., 2009). Inositol-depletion is one of the

hypotheses suggested for the mechanism of action of

mood stabilizers (Berridge et al., 1982; Berridge and

Irvine, 1989), arising from the observation that Li inhibits

glycogen synthase kinase-3b (GSK-3b) at a close-to-

therapeutic concentration (Klein and Melton, 1996). VPA

was also shown to inhibit GSK-3b activity (Phiel et al.,2001; De Sarno et al., 2002; Werstuck et al., 2004),

suggesting a common mechanism of action of these two

mood stabilizer drugs, as well as SB. Therefore, SB may

act as mood stabilizer by depleting inositol.

Another possible mechanism of action for the antimanic

effects of SB might be the upregulation of BDNF, as

described above. With regard to the pathogenesis of BD,

studies have shown a reduction in serum BDNF levels

during acute manic and depressive episodes (Tramontina

et al., 2007; Lin, 2009; Fernandes et al., 2011). In previous

studies from our laboratory, we have shown that BDNF was

decreased in animal models of mania induced by

D-AMPH or ouabain, whereas the mood stabilizers, Li or

VPA, reversed and prevented this alteration (Frey et al.,

2006a; Jornada et al., 2010). It has been widely shown that

chronic treatment with either of the mood stabilizers Li or

VPA increases BDNF, which is related to enhancement of

synaptic plasticity (Fukumoto et al., 2001; Einat et al., 2003).

Conclusion

The tricyclic compound, IMI, was used as a reference

drug in two animal models of depression, and mood

stabilizers, Li and VPA, were used as reference drugs in

two animal models of mania. SB showed antidepressant-

like activity and was as effective as IMI in preventing the

depressive-like behaviors. Likewise, SB was as effective

on the manic-like behaviors as Li and VPA. Taken

together, these observations support the hypothesis that

SB has a broader pharmacotherapeutic profile as an

antidepressant and antimanic agent. The possible me-

chanism of action of SB might involve, at least in part,

increase of neurotrophic factors (GDNF and BDNF) and

inositol depletion, contributing to brain development and

maturation. Considering that SB acts on a specific

molecular target we suggest that it may act more quickly,

be more effective and, consequently have fewer side-

effects than current medications. However, the disadvan-

tage to the use of SB or VPA is the possibility that its

direct target may play an important role in some side-

effects, such as teratogenicity or polycystic ovarian

disease (Phiel et al., 2001). Therefore, it is of the utmost

importance that more studies are performed to better

understand the effects of SB, and to establish criteria for

the use of this drug.

AcknowledgementsThe authors thank CNPq, FAPESC, CAPES, and

UNESC for financial support.

Conflicts of interest

There are no conflicts of interest.

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