European Journal of Pharmacology 702 (2013) 180186

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European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Behavioural pharmacology

Evidences for the involvement of sigma receptors in antidepressant

like effect of quetiapine in mice
Nandkishor R. Kotagale, Sachin M. Mendhi, Manish M. Aglawe, Milind J. Umekar, Brijesh G. Taksande n
Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, Maharashtra 441002, India

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 17 May 2012
Received in revised form
18 January 2013
Accepted 29 January 2013
Available online 8 February 2013

Although quetiapine is routinely used in the treatment of schizophrenia and bipolar disorders, the
precise mechanism of its antidepressant activity is poorly understood. Since quetiapine binds with
sigma receptor, the possibility exists that antidepressant action of quetiapine may be mediated through
interaction with sigma receptors. In the present study, quetiapine [4080 mg/mouse, intracerebroventricular (i.c.v.) and 40 mg/kg, intraperitoneal (i.p.)], sigma1 receptor agonist, ( )-pentazocine (120 mg/
mouse, i.c.v.) and sigma2 receptor agonist, PB-28 [1-Cyclohexyl-4-[3-(1,2,3,4-tetrahydro-5-methoxy-1naphthalenyl)propyl]piperazine] (20 mg/mouse, i.c.v.) signicantly decreased immobility time in forced
swim test. In combination studies, the antiimmobility effect of quetiapine (20 mg/mouse, i.c.v.) was
signicantly potentiated by pretreatment with ()-pentazocine (30 and 60 mg/mouse, i.c.v.) or PB-28
(5 and 10 mg/mouse, i.c.v.). Conversely, prior administration of sigma1 receptor antagonist, BD-1063 [1[2-(3,4-Dichlorophenyl)ethyl]-4-methylpiperazine] and sigma2 receptor antagonists, SM-21 [( 7 )Tropanyl 2-(4-chlorophenoxy)butanoate] antagonized the antiimmobility effect induced by quetiapine
and its synergistic combination with sigma receptor agonists. These results demonstrated the
involvement of sigma receptors in the antidepressant like effect of quetiapine and suggest that sigma
receptors can be explored as a potential therapeutic target for the treatment of depressive disorders.
& 2013 Elsevier B.V. All rights reserved.

Keywords:
Quetiapine
( )-Pentazocine
Sigma receptor
Depression
FST

1. Introduction
Quetiapine is an atypical antipsychotic routinely used for the
treatment of schizophrenia and bipolar disorders. The antipsychotic
effect of quetiapine has been linked with its antagonistic activity at
5-HT2 and dopamine D2 receptors (Gefvert et al., 1998). Antidepressant prole of quetiapine differentiates it from other typical and
atypical antipsychotic drugs (Calabrese et al., 2005; Thase et al.,
2006). The mechanism of this antidepressant activity is currently
unknown, however suggested to be partially associated with agonistic activity at 5HT1A receptors and increased prefrontal cortex
dopaminergic neurotransmission in brain (McIntyre et al., 2007). It
is now well accepted that dopaminergic neurotransmission plays an
important role in the pathogenesis of depression as the agents that
modulate dopamine function (precursors, agonists and reuptake
inhibitors) in the brain are reported to possess antidepressant
property (Kapur and Mann, 1992).
Quetiapine also binds with high afnity to sigma (s) receptors
(Guitart et al., 2004). Sigma receptors exists in two subtypes, sigma1
(s1) and sigma2 (s2) and proposed as a putative therapeutic target

Corresponding author. Tel.: 91 07109 288650; fax: 91 07109 287094.

E-mail addresses: b_taksande@rediffmail.com,
brijeshtaksande@gmail.com (B.G. Taksande).
0014-2999/$ - see front matter & 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ejphar.2013.01.045

for several psychiatric diseases including depression, anxiety, schizophrenia, drug addiction and neurodegenerative disorders (Cobos
et al., 2008; Guitart et al., 2004; Martin-Fardon et al., 2007; Maurice
and Romieu, 2004; Monnet and Maurice, 2006). Sigma receptors are
abundantly localized in brain areas implicated in the pathophysiology
of depression (Aan het Rot et al., 2009; Drevets et al., 2008) including
the hippocampus, frontal cortex, hypothalamus, and olfactory bulb
(Itzhak et al., 1985, 1991). The activation of s receptors by selective
or non-selective s receptors agonists including, dio-tolylguanidine
(DTG), igmesine, ()-pentazocine, SA 4503 and UMB23 produce
antidepressant like effect in animal models of depression (Matsuno
et al., 1996; Ukai et al., 1998; Skuza and Rogoz, 2002; 2003; Wang
et al., 2007b) possibly through modulation of glutamatergic, serotonergic, adrenergic and dopaminergic neurotransmission in brain
(Kobayashi et al., 1997; Matsuno et al., 1996; Wang et al., 2007a).
Conversely, pre-treatment with the s receptor antagonists BD 1047
[N-[2-(3,4-Dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine] or NE 100 [4-Methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine] abolished the antidepressant-like effect induced by
s receptors agonists (Matsuno et al., 1996; Wang et al., 2007b).
Further, s1 receptors knockout mice showed high immobility
response in the forced swim test (Sabino et al., 2009). It is important
to note that, several clinically used antidepressants and endogenous
neurosteroids with antidepressant activity such as pregnenolone
possessed afnity for s receptors (Dhir and Kulkarni, 2008;

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181

Fishback et al., 2010; Maurice and Romieu, 2004; Su et al., 1990).

Interestingly, quetiapine also exhibits strong afnity toward s
receptor (Guitart et al., 2004). However, the role of s receptors in
antidepressant like effect of quetiapine remained unexplored.
We hypothesized that antidepressant like effect of quetiapine
might involve modulation of s receptors. The present study
explored the involvement of s1 and s2 receptor subtypes in
antidepressant like effect of quetiapine using mouse forced
swim test.

At the end of the experiment, dilute India ink was injected by

i.c.v. route and the animals were euthanized by an overdose of
pentobarbital sodium (80 mg/kg, i.p.). Immediately, the brain of
mouse was dissected out and cannula placement was veried
histologically for distribution of ink in the ventricles. The guide
cannulae were found to be incorrectly placed in some animals
(15%) and these were excluded from the observations. Data from
only those animals with uniform distribution of ink in the
ventricles were considered for statistical analysis.

2. Materials and methods

2.4. Assessment of antidepressant activity

2.1. Subjects

2.4.1. Forced swim test

Forced swim test (FST) was performed to assess antidepressant
activity. The immobility time in FST was measured by the observer
blind to the treatment using procedure described by Porsolt et al.
(1977) with slight modication (Hirani et al., 2002; Taksande et al.,
2009). Briey, mice were placed individually in plexiglass cylinders
(21 cm height12 cm internal diameter) containing fresh water up
to a height of 9 cm at 251 1C and forced to swim for 15 min as
pretest session to maintain consistency in the basal immobility
time between different groups. After 24 h, the animals were
randomly divided into different groups (68 animals/group) and
treated with either a drug (test group) or vehicle (control group)
30 min before test session. Each mouse was again forced to swim
in a similar environment for the period of 6 min in a test session
and immobility time was measured. A mouse was judged to be
immobile when it remained oating motionless in the water,
making only necessary movements to keep its head above water.
Each mouse was used only once in test session. Reduction in the
duration of immobility was considered as antidepressant like effect
of the drug.

Male Swiss mice (2530 g) were housed under controlled

environmental condition at 2471 1C under 12:12 h light/dark
cycle (lights on 07:0019:00 h) during the experiment. Food and
water was available ad-libitum. All experimental procedures were
approved by Institutional Animal Ethical Committee and executed
according to guidelines given by Committee for the Purpose of
Control and Supervision of Experimental Animals (CPCSEA),
Ministry of Environment and Forests; Government of India;
New Delhi.
2.2. Drugs and administration
Quetiapine fumarate, ( )-pentazocine and PB 28 [1-Cyclohexyl-4-[3-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)propyl]piperazine], were obtained from Sigma chemicals, St. Louise, USA.
SM 21 maleate [(7)-Tropanyl 2-(4-chlorophenoxy)butanoate maleate] and BD 1063 [1-[2-(3,4-Dichlorophenyl)ethyl]-4-methylpiperazine] were obtained from Tocris Bioscience, Missouri, USA. All
drugs were dissolved in articial cerebrospinal uid (aCSF) [composition: 125 mM NaCl, 10 mM glucose, 1.25 mM NaH2PO4, 2.5 mM
CaCl2, 1.5 mM MgSO4, 26 mM NaHCO3, adjust pH to 7.4 with 0.1 M
NaOH] just before the experiments and infused by intra cerebroventricular (i.c.v.) route in volume of 2 ml/side bilaterally. For
intraperitoneal (i.p.) administration, drugs were dissolved in sterile
saline.
2.3. Intracerebroventricular (i.c.v.) cannula implantation
The detailed procedure for i.c.v. cannulation was described in
our previous report (Kotagale et al., 2010). Briey, mice were
anesthetized with an i.p. injection of pentobarbitone sodium
60 mg/kg. The guide cannulae (C315 GH/4/SPC, Plastic one Virginia, USA) was implanted bilaterally into the third ventricle using
stereotaxic coordinates, 70.7 mm posterior, 70.2 mm bi-lateral
to midline, 72 mm ventral from bregma (Paxinos and Franklin,
1997). A 28-gauge dummy cannula (C315 1H/4/SPC, Plastic one
Virginia, USA) was inserted to occlude the guide cannula when
not in use. After surgery, the animals were placed individually in
cages and allowed to recover for 7 days during which they were
handled to condition for future experimental procedure. They
were treated with oxytetracyclin (25 mg/kg, intramuscular) and
neosporin ointment to avoid any infection. The i.c.v. injections
were given by 33-guage internal cannula (internal diameter
0.18 mm and outer diameter 0.20 mm), which was attached to a
Hamilton microliter syringe (10 ml) via polyethylene tubing (PE10) (internal diameter, 0.28 mm; outer diameter, 0.61 mm), that
extended 0.5 mm beyond the guide cannula. The internal cannula
was held in position for another 1 min before being slowly
withdrawn to prevent backow and promote diffusion of drug
(Geiger et al., 2008).

2.5. Dose specic effect of quetiapine and s receptor ligands on

immobility time in FST
This experiment examined the dose dependent effect of
quetiapine, s receptor agonists or antagonists on immobility
time in FST. Different group of mice (n 6) were administered
with various doses of quetiapine [(10, 20, 40 mg/kg, i.p.); (20, 40,
80 mg/mouse, i.c.v.)] or saline (10 ml/kg, i.p.) or aCSF (2 ml/mouse,
i.c.v.). Thirty min later each mouse was subjected to FST for 6 min
and the duration of immobility was measured.
In separate group of experiments, mice (n 6) were treated
with either ( )-pentazocine (30, 60, 120 mg/mouse, i.c.v., s1
receptor agonist), PB-28 (5, 10, 20 mg/mouse, i.c.v., s2 receptor
agonist), BD-1063 (5, 10, 20 mg/mouse, i.c.v., s1 receptor antagonist), SM-21 (2.5, 5, 10 mg/mouse, i.c.v., s2 receptor antagonist) or
aCSF (2 ml/mouse, i.c.v.) and 30 min thereafter immobility time
was measured in the test session.

2.6. Inuence of s receptor agonists on quetiapine induced

antidepressant like effect
This experiment examined the antidepressant like effect of
quetiapine in animals pretreated with s1/ s2 receptor agonists.
For combination studies subeffective doses of drugs were used.
Different groups of mice were pretreated with ( )-pentazocine
(30 and 60 mg/mouse, i.c.v.) or PB-28 (5 and 10 mg/mouse, i.c.v.) or
aCSF (2 ml/mouse, i.c.v.). Thirty min following these treatments,
all animals received subeffective dose of quetiapine (20 mg/
mouse, i.c.v.) or aCSF (2 ml/mouse, i.c.v.) and the immobility time
was measured for 6 min test session in FST.

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2.7. Inuence of s receptor antagonists on antidepressant like effect

of quetiapine alone and receptors agonists combination
Mice were injected with BD-1063 (10 mg/mouse, i.c.v., s1
receptor antagonist) or SM-21 (5 mg/mouse, i.c.v., s2 receptor
antagonist) or aCSF (2 ml/mouse, i.c.v.) 30 min prior to administration of effective dose of quetiapine (40 mg/mouse, i.c.v.) or aCSF
(2 ml/mouse, i.c.v.). Thirty minutes thereafter forced swim test
was conducted as mentioned earlier.
Separate group of mice were injected with BD-1063 (10 mg/
mouse, i.c.v., s1 receptor antagonist) or SM-21 (5 mg/mouse, i.c.v.,
s2 receptor antagonist) or aCSF (2 ml/mouse, i.c.v.) prior to the
administration of per se non effective dose of quetiapine (20 mg/
mouse, i.c.v.) or aCSF (2 ml/mouse, i.c.v.) and ( )-pentazocine
(60 mg/mice, i.c.v., s1 receptor agonist) or PB-28 (10 mg/mouse,
i.c.v., s2 receptor agonist) or aCSF (2 ml/mouse, i.c.v.) and 30 min
thereafter FST was conducted.
2.8. Locomotor activity
This test was performed to assess whether drug effect on
immobility was associated with changes in motor activity. Locomotor activity was measured using actophotometer (20 cm 
20 cm  10 cm) (Techno, India) equipped with six infrared photo
sensors, 2.5 cm apart from each other. Mice were habituated to
the actophotometer chamber for 30 min before any testing.
Locomotor activity of each mouse was recorded for 10 min as a
total count of ambulatory, horizontal and vertical activity.
2.9. Data analysis
All data were presented as the mean 7SEM. To identify
signicant differences in dose dependant study of several drugs,
data were analyzed by one-way ANOVA followed by post-hoc
Dunnett or NewmanKeuls multiple comparison test or two-way
ANOVA followed by post-hoc Bonferroni mean comparisons.

3. Results
3.1. Quetiapine decreases immobility time in FST
Administration of quetiapine (40 mg/kg, i.p.) signicantly
decreased the immobility time as compared with saline treated
group [F(3, 20)6.48, p o0.01] (Fig. 1A). Post hoc Dunnett mean
comparison demonstrated that quetiapine (40 mg/kg, i.p)
(po0.01) signicantly decreased the immobility time while its
lower doses (10 and 20 mg/kg, i.p.) failed to inuence the
immobility time in FST.
Similarly, i.c.v. administration of quetiapine (4080 mg/mouse)
also reduced the immobility time as compared with aCSF treated
mice [F(3, 18) 6.49, p o0.01] [Fig. 1(B)]. Post hoc Dunnett mean
comparison showed the signicant reduction in the immobility
time in the animals injected with quetiapine [40 (p o0.05) and
80 mg/mouse (p o0.01)] as compared to control animals. However, its lower dose (20 mg/mouse, i.c.v.) was ineffective in FST.
3.2. Dose specic effect of s receptors ligands in FST
Fig. 2 illustrates the effect of ( )-pentazocine, PB-28, BD-1063
and SM-21 on immobility time in FST. ( )-pentazocine (120 mg/
mouse, i.c.v.) [F(3, 17)4.26, po0.05] and PB-28 (20 mg/mouse,
i.c.v.) [F(3, 18) 5.42, p o0.01] signicantly decreased the immobility time in FST. Post hoc Dunnett mean comparison showed the
signicant difference in the immobility time in the animals
injected with ( )-pentazocine (120 but not with 30 and 60 mg/

Fig. 1. Dose related antidepressant like effect of quetiapine in FST in mice. Mice
were treated with saline (10 ml/kg, i.p.) or quetiapine (1040 mg/kg, i.p.) or aCSF
(2 ml/mouse, i.c.v.) or quetiapine (2080 mg/mouse, i.c.v.) and subjected to FST
30 min after the treatments. Each bar represents mean immobility time
(s) 7S.E.M. (n 47). *-po 0.05, **-po 0.01 vs respective control animals (One
way ANOVA followed by post hoc Dunnet-test).

mouse) (p o0.05) and PB-28 (20 but not 5 and 10 mg/mouse)

(p o0.05) as compared to aCSF treated control animals. On other
hand, BD-1063 (520 mg/mouse, i.c.v.) and SM-21 (2.510 mg/
mouse, i.c.v.) did not show any signicant effect on the immobility time in FST as compared to aCSF treated control group (Fig. 2).

3.3. Sigma receptor agonists potentiates the antidepressant like

effect of quetiapine
Fig. 3 depicts the effects of a combination of per se non effective
dose of quetiapine and s1 or s2 agonists in FST. Pretreatment of
animal with ()-pentazocine (30 and 60 mg/mouse, i.c.v., s1
receptor agonist) or PB-28 (5 and 10 mg/mouse, i.c.v., s1 receptor
agonist) 30 min before quetiapine (20 mg/mouse, i.c.v.) resulted in a
signicant reduction in immobility time as compared to their
individual effects [Two way ANOVA: Fs receptor agonist treatment
(4, 41)2.92, po0.05; FQuetiapine treatment (1, 41)63.93, po0.001
and Fs receptor agonist x Quetiapine treatment (4, 41)1.38, p40.05].
Quetiapine, ()-pentazocine and PB-28 at the doses used here
alone did not produce any effect in FST as compared to control
animals (p40.05).

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183

Fig. 2. Dose dependent effects of s1 receptor agonist, ( )-pentazocine, s2 receptor agonist, PB-28, s1 receptor antagonist, BD-1063 and s2 receptor antagonist, SM-21 on
immobility time in FST. Mice were treated with aCSF (2 ml/mouse, i.c.v.) or ( )-pentazocine (30120 mg/mouse, i.c.v.), PB-28 (520 mg/mouse, i.c.v.), BD-1063 (520 mg/
mouse, i.c.v.) or SM-21 (2.510 mg/mouse, i.c.v.) 30 min prior to FST. Each bar represents mean immobility time (s) 7 S.E.M. (n 47). np o0.05 vs aCSF treated animals
(One way ANOVA followed by post hoc Dunnet-test).

Fig. 3. Effect of co-administration of per se non-effective doses of s1 receptor

agonist, ( )-pentazocine or s2 receptor agonist, PB-28 and quetiapine on
immobility time in FST. Separate group of mice were pre-treated with either aCSF
(2 ml/mouse, i.c.v.) or ()-pentazocine (30 and 60 mg/mouse, i.c.v.) or PB-28 (5 and
10 mg/mouse, i.c.v.) 30 min prior to administration of quetiapine (20 mg/mouse,
i.c.v.). Thirty minutes following last treatment animals were subjected to FST. Each
bar represents the mean immobility time (s) 7 S.E.M. (n 47). *-p o0.05,
**-p o 0.01 vs aCSF treatment, $- po 0.05 vs quetiapine treated animals (Two
way ANOVA followed by post hoc Bonferroni test).

3.4. s1 Receptor antagonist, BD-1063 and s2 receptor antagonist,

SM-21 antagonize the antidepressant like effect of quetiapine in FST
As shown in Fig. 4, pretreatment of mice with s1 receptor
antagonist, BD-1063 (10 mg/mouse, i.c.v.) [F(3, 18)9.09, po0.01]
or s2 receptor antagonist, SM-21 (5 mg/mouse, i.c.v.) [F(3, 20)
12.46, po0.001] completely blocked the antidepressant like effect

Fig. 4. Inuence of per se non- effective doses of s1 receptor antagonist, BD-1063

or s2 receptor antagonist, SM-21 pretreatment on the antidepressant like effect of
quetiapine. Separate group of mice were pre-treated with either aCSF (2 ml/mouse,
i.c.v.) or BD-1063 (10 mg/mouse, i.c.v.) or SM-21 (5 mg/ mouse, i.c.v.) 30 minutes
prior to administration of quetiapine (40 mg/mouse, i.c.v.) or aCSF (2 ml/mouse,
i.c.v.). Thirty minutes following last treatment animals were subjected to FST. Each
bar represents the mean immobility time (s) 7 S.E.M. (n 47). $p o 0.05 vs aCSF
treatment, *-p o 0.05, *-p o 0.01 vs quetiapine treated animals (One way ANOVA
followed by post hoc NewmannKeuls test).

induced by quetiapine. Post hoc Dunnetts mean comparisons

demonstrated that BD-1063 (po0.01) or SM-21 (po0.001) pretreatment signicantly reduced the anti-immobility effect of quetiapine in FST.
In separate groups, BD-1063 (10 mg/mouse, i.c.v.) or SM-21
(5 mg/mouse, i.c.v.) pretreatment respectively abolished the
synergistic antidepressant like effect exhibited by quetiapine
and ( )-pentazocine [F(3, 21) 35.83, p o0.001] or PB-28 [F(3,

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N.R. Kotagale et al. / European Journal of Pharmacology 702 (2013) 180186

Fig. 5. Inuence of per se non-effective doses of s1 receptor antagonist, BD-1063

or s2 receptor antagonist, SM-21 pretreatment on the antidepressant like effect of
quetiapine and s1 receptor agonist, ()-pentazocine or s2 receptor agonist,
PB-28. Separate group of mice were pre-treated with either aCSF (2 ml/mouse,
i.c.v.) or BD-1063 (10 mg/mouse, i.c.v.) or SM-21 (5 mg/mouse, i.c.v.) 30 min prior
to coadministration of quetiapine (20 mg/mouse, i.c.v.) and aCSF (2 ml/mouse,
i.c.v.) or ()-pentazocine (60 mg/mouse, i.c.v.) or PB-28 (10 mg/mouse, i.c.v.) and
were subjected to FST. Each bar represents the mean immobility time (s) 7 S.E.M.
(n 47). $-p o 0.001 vs aCSF treatment, n-po 0.001 vs ( )-pentazocine
quetiapine treatment, #-p o0.001 vs PB-28 quetiapine treated animals (one
way ANOVA followed by post hoc NewmannKeuls test).

22) 32.29, p o0.001] combination. Quetiapine, ( )-pentazocine,

PB-28, BD-1063 or SM-21 at the doses used here alone did not
inuence the immobility time in FST (Fig. 5)
3.5. Inuence of quetiapine, s receptor agonists and antagonists on
ambulations and rearings in open eld test and locomotor activity
Quetiapine, s1/s2 receptor agonists or antagonists alone or in
combination at different doses used in this study did not produce
any effect on locomotor activity in actophotometer. In saline/aCSF
treated control animals the total count of ambulations was
(110.2712.25, n 6) (data not shown).

4. Discussion
Although quetiapine is regularly used for the treatment of
schizophrenia and depressive illness, precise mechanism for its
antidepressant activity is poorly understood. The key observation
of this study is that antidepressant like effect of quetiapine is
derived from an interaction of quetiapine with s receptors in
brain. Two subtypes of s receptors, s1 and s2, have been
identied, and are differentiated according to their molecular
weights, tissue distributions, and pharmacological proles
(Hellewell and Bowen, 1990; Quirion et al., 1992; Hellewell
et al., 1994; McCann et al., 1994). In the brain, s receptors are
enriched in limbic and endocrine areas that have been implicated
in the pathophysiology of depression (Drevets et al., 2008; Aan
het Rot et al., 2009), including the hippocampus, frontal cortex,
hypothalamus, and olfactory bulb (Itzhak et al., 1985). Numerous
studies indicated that s receptor agonists including: dio- tolylguanidine (DTG), igmesine, ()-pentazocine, SA 4503, and
UMB23 (1-(3-phenylpropyl) piperidine oxalate) (Matsuno et al.,
1996; Wang et al., 2007b) produce antidepressant like effects in

animals and humans (Matsuno et al., 1996; Ukai et al., 1998;

Skuza and Rogoz, 2002; 2003; Wang et al., 2007b). On the other
hand, pre-treatment with the s receptor antagonists like BD 1047
or NE 100 abolished the antidepressant like action of s receptor
agonists (Matsuno et al., 1996; Wang et al., 2007a). Studies with
s1 receptor knockout mice further support their role in depression as these animals present a depression-like response in the
FST (Sabino et al., 2009). Further, s receptor agonists modulate
the activities of the neurotransmitter systems, signaling pathways
and brain regions implicated in the pathophysiology of depression (Bermack and Debonnel, 2005; Lu et al., 2012; Kobayashi
et al., 1997; Wang et al., 2007a). Importantly most of the
marketed antidepressant drugs bind to s receptors, raising the
possibility that some of their therapeutic effects might be
mediated through its activation (Itzhak and Kassim., 1990;
Narita et al., 1996). In addition to the these classical antidepressants, some endogenous neurosteroids such as dehydroepiandrosterone (DHEA) and pregnenolone produced antidepressant
activity via s receptors modulation (Su et al., 1990; Maurice and
Romieu, 2004; Dhir and Kulkarni, 2008). Thus it is conceivable
that s receptors may be potential therapeutic target for antidepressant action of several clinically available antidepressant
agents. In our study, the antiimmobility effect of quetiapine was
dose dependently augmented by s1 receptor agonist, ( )-pentazocine and s2 receptor agonist, PB-28. This observation suggests
possible interaction between s receptors and quetiapine for
induced antidepressant like effect in mouse FST. It is worth noting
that quetiapine possesses high afnity for s receptors (Guitart
et al., 2004). It could therefore be argued that, antidepressant
activity of quetiapine might be directly linked to agonistic activity
at s receptors subtypes in brain.
Further antiimmobility effect of quetiapine was investigated in
presence of s receptor antagonists. We found that antagonists of
s1 and s2 receptor, BD-1063 and SM-21 (respectively) completely blocked the antiimmobility effect of quetiapine. These s
receptor antagonists also completely blocked the synergistic
antidepressant effect observed following combination of s receptor agonists and quetiapine. This strengthens our assumption
that antidepressant like effect of quetiapine is mediated via
interaction with s receptors. The antidepressant like effect
quetiapine or s receptor agonists was not due to any locomotor
component since the locomotor counts in actophotometer
remained unaffected. Another important consequence of the
study is that it increases the validity of the model, since it detect
the antidepressant-like effect of quetiapine, an atypical
antidepressant drug.
Quetiapine induced antidepressant like effect was attributed
to 5-HT1A agonism and facilitation of dopamine neurotransmission in brain (McIntyre et al., 2007). Several ndings have
suggested the role of dopaminergic systems, particularly deciency of mesolimbic dopamine in pathophysiology of depression
(Nestler and Carlezon, 2006); see review (Finan and Smith, 2012).
Further, compromised nigrostriatal dopaminergic transmission is
implicated in the etiology of psychomotor retardation, a symptom
characteristic of depressive states (Martinot et al., 2001). Moreover drastic reduction in levels of dopamine and its metabolite
homovanillic acid in cerebrospinal uid of depressed patients
were already reported (Sher et al., 2003). Consequently, the drugs
which increased dopamine levels in brain either by inhibiting the
dopamine reuptake (e.g. bupropion or nomifensine) or dopaminergic agonistic action have been shown to possesses antidepressants activity (Kapur and Mann, 1992) and many antidepressants
sensitize the mesolimbic dopaminergic pathways and strengthen
dopaminergic signaling in the nucleus accumbens (Dhir and
Kulkarni, 2007) to induced antidepressant action. It is worthwhile
to mention here that s receptors are involved in the modulation

N.R. Kotagale et al. / European Journal of Pharmacology 702 (2013) 180186

of dopamine release in the rat brain. Intraperitoneal or subcutaneous injection of the s receptor agonists, ( )-pentazocine, DTG
or SKF 10,047 increases extracellular dopamine in the striatum
and medial prefrontal cortex of freely moving animals (Patrick
et al., 1993; Gudelsky, 1995). This effect is suggested to be s
receptor mediated because its antagonist, NE 100 abolished the
dopamine release resulting from acute oral administration of s
receptor agonist, SA 4503 (Kobayashi et al., 1997). Quetiapine
binds with s receptors and facilitates dopaminergic neurotransmission in brain; it is therefore possible that quetiapine might
activate s receptors to increase dopamine release in prefrontal
cortex and striatum to exhibits antidepressant like effect. This is
also supported by the fact that many antidepressants like uoxetine (a selective serotonin re-uptake inhibitor) or desipramine
(a potent inhibitor of the noradrenaline re-uptake carrier) also
increase the extracellular dopamine concentration in the prefrontal cortex associated with their therapeutic efcacy (Tanda
et al., 1994, 1996). However there should be a counterpoint as
quetiapine also possess antagonistic activity toward dopamine D2
receptors (Gefvert et al., 1998). Therefore, this issue needs to be
claried using more specic analytical techniques and pharmacological manipulations. The interaction between quetiapine and
s receptors can also activate glutamatergic, adrenergic and
serotonergic systems (Matsuno et al., 1996; Wang et al., 2007a;
Kobayashi et al., 1997) and their involvement in antidepressant
like effect of quetiapine cannot be completely ruled out.
In summary, present study for the rst time provides direct
functional evidences for the involvement of s receptors subtypes
in antidepressant like effect of quetiapine. The antiimmobility
effect of quetiapine in FST was potentiated by s receptor agonists,
( )-pentozocine and PB-28 respectively. On the other hand, this
antidepressant like effect of quetiapine was completely attenuated in presence of s receptor antagonists, SM-21 and BD-1063.
In addition, s receptor antagonists also blocked the antidepressant effect of quetiapine and ()-pentozocine or PB 28 combination. These results clearly demonstrated the involvement of s
receptors subtypes in the antidepressant like effect of quetiapine
and suggest that s receptors can be projected as a potential
therapeutic target for the treatment of depressive illness.
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