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Progress in Neuro-Psychopharmacology & Biological Psychiatry 41 (2013) 11–17
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Progress in Neuro-Psychopharmacology & Biological
Psychiatry
journal homepage: www.elsevier.com/locate/pnp
Modulation of ventral tegmental area dopamine receptors inhibit nicotine-induced
anxiogenic-like behavior in the central amygdala
Mohammad Reza Zarrindast a,b,c,d,⁎, Nafiseh Eslahi e, Ameneh Rezayof f, Parvin Rostami e, Maryam Zahmatkesh a
a
Department of Neuroscience, School of Advanced Technologies in Medicine and Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran
School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
d
Institute of Cognitive Science Studies (ICSS), Tehran, Iran
e
Department of Animal Biology, School of Biology, Tarbiat Moalem University, Tehran, Iran
f
Department of Animal Biology, School of Biology and Center of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran
b
c
a r t i c l e
i n f o
Article history:
Received 13 May 2012
Received in revised form 5 September 2012
Accepted 14 September 2012
Available online 21 November 2012
Keywords:
Anxiety
Central amygdala
Elevated plus maze
Nicotine
Ventral tegmental area
a b s t r a c t
Nicotine, the major addictive substance in tobacco, increases the activity of the central amygdala (CeA).
Amygdala is directly implicated in anxiety modulation and sends projections to the vicinity of the midbrain
dopamine neurons, including the ventral tegmental area (VTA) which is a key area that controls nicotine dependence processes. In this study, the role of dopamine D1 and D2/3 receptors of the VTA on anxiogenic-like
behavior induced with intra-CeA injection of nicotine has been investigated. Male Wistar rats with cannula
aimed to the left CeA and the left VTA were submitted to the elevated plus-maze (EPM). The nicotine injection (1 μg/rat) into the CeA decreased the percentage of open arm time and open arm entries, but not locomotor activity, indicating an anxiogenic-like response. Intra-VTA injection of a dopamine D1 receptor
antagonist, SCH23390 (0.25 μg/rat), and a dopamine D2/3 receptor antagonist, sulpiride (0.7 μg/rat),
inhibited the anxiogenic-like response caused by intra-CeA injection of nicotine. These results suggest that
the relationship between the VTA and the CeA may be involved in nicotine-induced anxiogenic-like behavior
via dopamine D1 and D2/3 receptors. An understanding of these cellular processes will be crucial for the development of new intervention to combat nicotine effect.
© 2012 Published by Elsevier Inc.
1. Introduction
Nicotine, the major addictive substance in tobacco increases the
activity of reward related brain areas, such as the central amygdala
(CeA) and the nucleus accumbens (Brunzell et al., 2003; Pagliusi et
al., 1996; Pich et al., 1997). It is believed that amygdala directly modulates anxiety (Kalin et al., 2004; Lesscher et al., 2008) and provides
the main input to the dopamine neurons (Cassell et al., 1986;
Hopkins, 1975; Price and Amaral, 1981). The CeA also sends projections to the vicinity of the midbrain dopamine neurons (Fudge and
Haber, 2000; Wallace et al., 1992), including the ventral tegmental
area (VTA), which is a key region that regulates nicotine dependence
processes (Corrigall et al., 1994; David et al., 2006; Ikemoto et al.,
2006). Furthermore, nicotine increases the firing rate of VTA dopamine neurons (Grenhoff et al., 1986; Li et al., 2011; Schilstrom et al.,
2003) and modulates anxiety (Benowitz, 2008). The expression of
Abbreviations: VTA, ventral tegmental area; CeA, central amygdala; EPM, elevated
plus-maze; %OAT, the percentage of open arm time; %OAE, the percentage of open
arm entries.
⁎ Corresponding author at: Department of Neuroscience, School of Advanced Technologies
in Medicine, Tehran University of Medical Sciences, Ghods Street, Italia St./1417755469,
Tehran, Iran. Tel.: +98 21 88991118 20; fax: +98 21 88991117.
E-mail address: [email protected] (M.R. Zarrindast).
0278-5846/$ – see front matter © 2012 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.pnpbp.2012.09.004
nicotinic acetylcholine receptor (nAChR) alpha2 subunit in rat amygdala has been reported (Ishii et al., 2005). Central nAChRs are particularly presynaptic and exert a modulatory influence (Role and Berg,
1996) on neurotransmitter release (Dajas-Bailador and Wonnacott,
2004). For instance, the activation of presynaptic nAChRs modulates
glutamatergic and GABAergic synaptic transmission in the amygdala
(Barazangi and Role, 2001).
In most studies, nicotine is administered systemically or peripherally (for review see Matta et al., 2007), whereas central administration studies in animals help identify the involvement of specific
brain area in the anxiogenic and anxiolytic actions of nicotine.
While, there is a report of interaction between the CeA and the VTA
in the acquisition of conditioned cue-directed behavior (Lee et al.,
2011), little is known about the interaction between the CeA and
the VTA on anxiety-related behavior in the EPM test.
Dopamine is a key neurotransmitter involved in reward (Koob,
1992) and dopamine receptors consist of two families, D1-like (D1
and D5) and D2-like (D2, D3 and D4) (Sibley et al., 1993). Dopamine
D1 receptors are expressed in moderate to low density in the VTA
(Ariano et al., 1997) and the local perfusion of D1 receptor agonists
in the VTA increases the local release of both glutamate and GABA
(Kalivas and Duffy, 1995), which can control the activity of dopamine
neurons (Adell and Artigas, 2004). Furthermore, the dopamine D2
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M.R. Zarrindast et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 41 (2013) 11–17
receptors are highly expressed in the VTA of rodents (Mansour et al.,
1990; Wamsley et al., 1989). Activation of D2 autoreceptors leads to
increased potassium conductance that hyperpolarizes the plasma
membrane of dopaminergic neurons (Adell and Artigas, 2004). It
has been shown that dopamine dendritic release regulates the firing
rate of dopaminergic neurons in the VTA through D2 receptors located
in the glutamatergic nerve ending (Koga and Momiyama, 2000).
In the present study, the possible involvement of dopamine D1
and D2/3 receptors of the VTA on anxiogenic-like behavior induced
with intra-CeA injection of nicotine has been investigated. The
SCH23390, as a dopamine D1 antagonist (Hyttel, 1983; Iorio et al.,
1983), and sulpiride as a dopamine D2/3 antagonist (Rüther et al.,
1999) have been used. The anxiety parameters have been assessed
by the elevated plus-maze (EPM) task. According to the definition
of Pellow and File in 1986, an anxiolytic drug is the one that increases
the number of entries into and the time spent in the open arms and
the opposite state is true by an anxiogenic drug.
2.4. Behavioral testing (elevated plus maze)
2. Experimental procedures
Measurements were conducted according to the method of Pellow
and File, 1986. The wooden tool consisted of two open arms
(50 cm × 10 cm), and two closed arms of the same size but with
40 cm high end and side walls. The arms were linked by a central
10 × 10 cm area. After 1 hour adaptation to the testing room, the
rats were located in the center of the plus maze with their head facing
an open arm and left undisturbed for 5 min. Before the next rat was
tested, the maze was cleaned with a 10% chlorine bleach solution
and dried with a cloth.
The experimental sessions were recorded on tape and analyzed
later. A rat was considered to be on the central platform when at least
two paws were on it and on an arm whenever all four paws were on
it. Percent time spent in open arms [%OAT: (time in open arm / time
in “open + closed” arm)× 100] and percent of open arm entries
[%OAE: (number of open arm entries / number of “open + closed” arm
entries)× 100] were considered as an anxiety index. The spontaneous
locomotor activity was calculated with the number of total arm entries.
2.1. Drugs
2.5. Experimental procedure
Nicotine hydrogen tartrate was purchased from Sigma (Poole,
Dorset, UK), SCH23390 from Tocris, UK and sulpiride from Sigma
Chemical Company (St. Louis, CA, USA). Immediately before the experiment, SCH23390 and nicotine were dissolved in sterile normal
saline. Sulpiride was dissolved in one drop of glacial acetic acid and
made up to a volume of 5 ml with sterile 0.9% saline and then diluted
to the required concentration. The pH of the solutions was adjusted
to 7.2 with NaOH (0.1 N solution). The volume of the drug injection
was 0.2 μl/rat. Drug total doses were expressed as μg/rat. Saline
was injected to control animals instead of drug solution.
2.5.1. Experiment 1: Intra-CeA injection of nicotine on anxiety-related
behavior in the EPM test
In the first experiment, after 5 minute saline injection into the
VTA, the different doses of nicotine (0.5, 1 and 1.5 μg/rat) were
injected into the CeA. The percent time spent in open arms (%OAT),
the percent of open arm entries (%OAE) and the locomotor activity
were measured 5 min after the injections.
2.2. Animals
The study was performed on male Wistar rats weighing between
220 and 250 g at the time of the surgery which were housed in
groups of 2–3 per cage on a 12/12 h light/dark cycle. All rats received
standard laboratory rat chow and water ad libitum. A total of eight
animals were used in each group (n = 8) and each animal was used
only once. All procedures were conducted in adherence with the institutional guidelines for animal care and use. The Research and Ethics
Committee of the School of Medicine, Tehran University of Medical
Sciences approved the experimental protocols.
2.5.2. Experiment 2: Intra-VTA injection of sulpiride on anxiety-related
behavior in the EPM test in the presence or absence of nicotine
The rats received intra-VTA injection of different doses of sulpiride
(0.2, 0.3, 0.5, 0.7 and 1 μg/rat) in combination with intra-CeA injection of an effective dose of nicotine (1 μg/rat) or saline.
2.5.3. Experiment 3: Intra-VTA injection of SCH23390 on anxiety-related
behavior in the EPM test in the presence or absence of nicotine
The rats received intra-VTA injection of different doses of SCH23390
(0.125, 0.25, 0.5 μg/rat) in combination with intra-CeA injection of saline. In part 2, the rats received intra-VTA injection of effective (0.125,
0.5 μg/rat) and sub-effective (0.25 μg/rat) doses of SCH23390 in combination with intra-CeA injection of an effective dose of nicotine
(1 μg/rat).
Experimental groups:
2.3. Surgery and microinjection
5 min
5 min
Intra VTA saline →
Intra CeA saline →
EPM test
The animals were anesthetized with 50 mg/kg ketamine hydrochloride plus 4 mg/kg xylazine intraperitoneally and placed on a stereotaxic
frame, and the skull was exposed. The stainless-steel guide cannula was
directed toward the left VTA and the left CeA. It was fixed with
polyacrylic cement anchored to the skull with stainless-steel screws.
Coordinates for cannulae implantation (Paxinos and Watson, 2007) in
the VTA were: anterocaudal: −5.8 mm; lateral: ±0.7 mm (both with
respect to bregma); and vertical: 8 mm (from dura), and coordinates
for the CeA were: anterocaudal: −2.3 mm; lateral: ±4.1 mm (both
with respect to bregma); and vertical: 8.1 mm (from dura). The animals
were allowed 7 days to recover before the test. For drug injection, the
animals were held gently, and the injection cannula extending
1.0 mm beyond the ventral tip of the implanted guide cannula was
gently inserted into each cannula and connected with polyethylene tubing to a 1-μl Hamilton syringe. The drug solution was injected over
1 min. Each rat received 0.2 μl injection solution into the CeA and the
VTA on the left side. After the injection, the injection cannulae were
left in place for an additional 1 min in order to minimize leakage up
the cannula track.
5 min
5 min
Intra VTA saline → Intra CeA nicotine ð0:5; 1&1:5 μg=ratÞ → EPM test
5 min
5 min
Intra VTA sulpiride ð0:2; 0:3; 0:5; 0:7 &1 μg=ratÞ → Intra CeA saline → EPM test
5 min
5 min
Intra VTA sulpiride ð0:3; 0:5; 0:7 μg=ratÞ → Intra CeA nicotine ð1 μg=ratÞ → EPM test
5 min
5 min
Intra VTA SCH23390 ð0:125; 0:25; 0:5 μg=ratÞ →Intra CeA saline →EPM test
5 min
5 min
Intra VTA SCH23390ð0:125; 0:25; 0:5 μg=ratÞ →Intra CeA nicotine ð1 μg=ratÞ →EPM test
2.6. Histology
At the end of the experimental period the drug injection site was
verified by methylene blue (1%) injection in the same volume as
drug injections. The animals were sacrificed with anesthetic overdose, their brains were removed and injection sites were verified histologically according to Paxinos and Watson (2007) atlas. Cannulae
were implanted for a total of 204 animals, but only the data from
192 animals with correct cannulae implants were included in the statistical analyses.
M.R. Zarrindast et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 41 (2013) 11–17
13
2.7. Statistical analysis
Analysis of the data was performed using one-way analysis of variance (ANOVA). Following a significant F-value, Tukey post-hoc analysis test was performed to assess specific group comparisons. The null
hypothesis was rejected at the 0.05 level of significance. Data were
expressed as mean ± SEM.
3. Results
Fig. 1 shows the approximate point of the drug injections in the
CeA and the VTA. The histological results were plotted on the representative section taken from the rat brain atlas of Paxinos and
Watson (2007). Data from the animals with the injection sites located
outside the CeA and the VTA were not used in the analysis.
3.1. Effects of three doses of nicotine on rat behavior in the EPM
As shown in Fig. 2, the intra-CeA injection of nicotine (1 μg/rat)
exerted a significant reduction in %OAT [F (3, 28) = 13.1, P b 0.001]
and %OAE [F (3, 28) = 5.26, P b 0.05] compared to saline + saline
group. No significant change in the locomotor activity [F (3, 28) =
0.4, P >0.05] was observed. The data showed that the maximum effect
was obtained with 1 μg/rat of nicotine, while the injection of 0.5 and
1.5 μg/rat of nicotine had no significant effect on the anxiety-related
parameters in the EPM.
3.2. Effects of sulpiride on rat behavior in the EPM
As shown in Fig. 3, intra-VTA injection of sulpiride (0.2, 0.3, 0. 5,
0.7 and 1 μg/rat) had no significant effect on %OAT [F (5, 42) = 0.91,
P > 0.05], %OAE [F (5, 42) = 2.79, P > 0.05] and locomotor activity
[F (5, 42) = 0.79, P > 0.05] compared to saline + saline group.
Intra-VTA injection of sulpiride (0.7 μg/rat) with intra-CeA injection of an effective dose of nicotine (1 μg/rat) significantly increased
%OAT [F (4, 35) = 8.41, P b 0.001] and %OAE [F (4, 35) = 3.87, P b 0.05]
compared to saline + nicotine group. As shown in Fig. 4, locomotor
activity [F (4, 35) = 0.506, P > 0.05] showed no significant changes
compared to saline + nicotine group (Fig. 4).
Fig. 2. Effects of intra-amygdala (CeA) nicotine injection on rat behavior in the EPM.
Nicotine (0.5, 1 and 1.5 μg/rat) was injected 5 min before the EPM test. Each bar represents mean ± S.E.M. of %Open arm time, %Open arm entries or locomotor activity.
Significant differences: ***P b 0.001 and *P b 0.05 compared to saline + saline group.
3.3. Effects of SCH23390 on rat behavior in the EPM
Fig. 1. Schematic illustrations of the coronal sections of the rat brain showing the approximate location of the CeA and the VTA injection sites in the experiments. The numbers
indicate A–P coordinates relative to bregma.
Atlas plates adapted from Paxinos and Watson (2007).
In Fig. 5, the effects of intra-VTA injection of different doses of
SCH23390 (0.125, 0.25, 0.5 μg/rat) were shown. The dose of 0.5 μg/rat
significantly increased the %OAT [F (3, 28)= 4.8, P b 0.05] and %OAE
[F (3, 28)= 3.2, P b 0.05] compared to saline+ saline group. The treatment had no effect on the locomotor activity [F (3, 28) = 0.27,
P>0.05]. It should be considered that the dose of 0.125 and 0.25 μg/rat
had no significant effect on the %OAT and %OAE compared to saline+
saline group.
Intra-VTA injection of sub-effective dose of SCH23390 (0.25 μg/rat)
with intra-CeA injection of an effective dose of nicotine (1 μg/rat)
significantly increased %OAT [F (4, 35) = 21.34, P b 0.01] and %OAE
[F (4, 35) = 11.82, P b 0.01] compared to saline + nicotine group.
The response of the antagonist not only inhibited anxiogenic-like
effect of nicotine, but also produced an anxiolytic-like effect. No
significant changes were shown in locomotor activity [F (4, 35) =
0.67, P > 0.05] compared to saline + nicotine group (Fig. 6).
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M.R. Zarrindast et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 41 (2013) 11–17
Fig. 3. Effect of intra-VTA sulpiride injection on rat behavior in the EPM. The animals
received intra-VTA injection of sulpiride. After 5 min, they received intra-CeA injection
of saline. Each bar represents mean ± S.E.M. of %Open arm time, %Open arm entries or
locomotor activity.
Fig. 4. Effects of intra-VTA injection of sulpiride in combination with intra-CeA injection of nicotine on rat behavior in the EPM. The animals received intra-VTA injection
of saline or sulpiride, after 5 min, they received intra-CeA injection of saline or an effective dose of nicotine (1 μg/rat). Each bar represents mean ± S.E.M. of %OAT, %OAE
or locomotor activity. Significant differences: *P b 0.05 and **P b 0.01, compared to
saline + saline group. +++P b 0.001 and +P b 0.05 compared to saline + nicotine
group.
4. Discussion
The present findings indicate that nicotine injection into the central
amygdala (CeA) decreased % open arm time spent (%OAT) and % open
arm entries (OAE %) in the elevated plus maze (EPM) test, suggesting
an anxiogenic-like effect. Although, this is consistent with previous
studies showing an anxiogenic-like effect following the systemic administration of nicotine (Foulds et al., 1997; Plaza-Zabala et al., 2010;
Zarrindast et al., 2010), there is less investigation regarding the effects
of central administration of nicotine on anxiety-related behavior
(Zarrindast et al., 2008). In the present experiment, nicotine was infused into the CeA and a U-shaped dose–response curve was observed.
The maximum effect was obtained with 1 μg/rat of nicotine, which was
considered as a nicotine effective dose. When peripherally administered, nicotine can exhibit an inverted U-shaped dose–response curve
(for review see Picciotto, 2003). It seems that low and higher doses of
nicotine produce anxiolytic- and anxiogenic-like effects respectively
(for review see Matta et al., 2007). The effects of nicotine are complex
and there are certain discrepancies between studies, which may be attributable, in part, to the different doses, injection sites, or routes of nicotine administration.
Moreover, amygdala has a direct role in anxiety modulation (Kalin
et al., 2004; Lesscher et al., 2008; Roozendaal et al., 2009) and there is
evidence indicating anxiogenic and anxiolytic effects following the
intra-amygdala infusion of D1 agonists and antagonists respectively
(de la Mora et al., 2010). Nicotine has long been known to modulate
synaptic transmission and plasticity in the amygdala (FU et al.,
1998; Mansvelder et al., 2009) and acute nicotine has been shown
to increase c-fos mRNA expression, a marker for neuronal activation
(Herrera and Robertson, 1996), in many brain regions, including the
CeA (Salminen et al., 1999).
Considering the release of dopamine by nicotine (Di Chiara, 2000;
Fu et al., 2000; Markou, 2008; Picciotto, 1998), it may be possible that
intra-CeA injection of nicotine induces anxiogenic-like effect directly
or indirectly through the dopamine receptors.
M.R. Zarrindast et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 41 (2013) 11–17
Fig. 5. Effects of intra-VTA injection of SCH23390 on rat behavior in the EPM. The animals received intra-VTA injection of saline or SCH23390, after 5 min, they received
intra-CeA injection of saline. Each bar represents mean ± S.E.M. of %OAT, %OAE or locomotor activity. Significant differences: *P b 0.05, compared to saline + saline group.
Several studies reported that the amygdala provides the main input
to dopamine neurons (Hopkins, 1975; Price and Amaral, 1981). Dopamine secretion within the nucleus accumbens through the VTA stimulation is essential for the nicotine reinforcing effects (Corrigall et al., 1992).
It has been reported that electrical stimulation of the VTA caused neural
discharge in the CeA and a fundamental link between the VTA activation
and neural excitability in the CeA, has been suggested (Gelowitz and
Kokkinidis, 1999). However, experimental support for the CeA and the
VTA interaction in nicotine-induced anxiety has been scarce.
In the present study, intra-CeA injection of nicotine showed an
anxiogenic-like response which was inhibited by the intra-VTA injection of sulpiride. It has been shown that dopamine can be released
from the cell body and dendrites in addition to axon terminals
(Björklund and Lindvall, 1975). Dopamine containing neurons in VTA
are about 60% (Margolis et al., 2006). Moreover, the extracellular pool
15
Fig. 6. Effects of intra-VTA injection of SCH23390 in combination with intra-CeA injection of nicotine on rat behavior in the EPM. The animals received intra-VTA injection of
saline or SCH23390, after 5 min, they received intra-CeA microinjection of an effective
dose of nicotine (1 μg/rat). Each bar represents mean ± S.E.M. of %OAT, %OAE or locomotor activity. Significant differences: *P b 0.05, **P b 0.01 and ***P b 0.001 compared
to saline + saline group. +++P b 0.001 and ++P b 0.01 compared to saline + nicotine
group.
of dopamine can activate local inhibitory D2 autoreceptors (White and
Wang, 1984) which are highly expressed in the VTA of rodents
(Mansour et al., 1990; Wamsley et al., 1989). Activation of the D2
autoreceptors leads to increased potassium conductance that hyperpolarizes the plasma membrane of dopaminergic neurons (Adell and
Artigas, 2004). It has also been shown that, 89% of dopaminergic neurons and 40% of non-dopamine neurons that project to the NAc are
inhibited by D2 receptor activation (Yim and Mogenson, 1980). However, Margolis et al. (2008) showed that amygdala-projecting VTA dopamine neurons are not inhibited by D2 receptor agonists and it is
unlikely that intra-VTA injection of sulpiride in the present study
could enhance dopamine impulse flow of meso-amygdala dopamine
cells.
Under control conditions, the VTA dopaminergic neurons receive
balanced inhibitory and excitatory inputs (Yang et al., 2009). Nicotine
16
M.R. Zarrindast et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 41 (2013) 11–17
activates CeA (FU et al., 1998; Mansvelder et al., 2009; Salminen et al.,
1999), and activation of presynaptic nAChRs modulates glutamatergic
and GABAergic synaptic transmission (Barazangi and Role, 2001). In
addition, the CeA projects to the vicinity of dopamine cell bodies in
VTA (Fudge and Haber, 2000; Wallace et al., 1992) which control
the mesocorticolimbic dopamine system (Phillips et al., 2003). It
may be predicted that intra-CeA nicotine injection in the present
study leads to a change of output from the CeA to VTA. However,
whether the intra-CeA nicotine injection leads to a reduction in VTA
dopamine impulse flow is not clear and this issue should be clarified
by further experiments. The somatodendritic dopamine release in the
mesocorticolimbic system is mainly dependent on the nerve impulse
activity in the VTA (Adell and Artigas, 2004; Chen and Rice, 2002;
Rice et al., 1997) and regulates the firing rate of dopaminergic neurons in the VTA through D2 receptors located in the glutamatergic
nerve ending (Koga and Momiyama, 2000). In the presence of
sulpiride, the roles of D2 receptors are blocked. We suggest that
sulpiride ability to inhibit anxiogenic activity of nicotine may be related to inactivation of local inhibitory D2 autoreceptors.
Furthermore, in the present study, intra-VTA injection of
0.25 μg/rat of SCH23390 which had no effect by its own increased
%OAT and %OAE and hence blocked the anxiogenic effect of
intra-CeA nicotine injection. The response of the antagonist not
only inhibited the anxiogenic effect of nicotine, but also produced
an anxiolytic effect. Local perfusion of D1 receptor agonists in the
VTA increases the local release of both glutamate and GABA (Kalivas
and Duffy, 1995), which can control the activity of dopamine neurons
(Adell and Artigas, 2004). The activation of D1 receptors located on
the VTA dopaminergic neurones or non-dopaminergic nerve terminals
increases D2 receptor-mediated inhibition via inhibitory neurons
(Momiyama et al., 1993). Therefore, the effects of SCH23390 and
sulpiride in the present study were in the same direction.
Moreover, serotonergic neurons modulate the function of dopamine neurons through the 5-HT receptor subtype, which is also
expressed in the VTA. It has been shown that 5-HT2C receptor agonists block the stimulatory action of nicotine on midbrain dopamine
function and thus reduce its reinforcing effects (Fletcher et al.,
2008; Lanteri et al., 2008). Furthermore, SCH23390 is also a potent
agonist at 5-HT2c receptors (Millan et al., 2001), therefore, its counteract nicotine effect in the present study, may be attributable, in
part, to its effect on VTA 5-HT2c receptors.
Although, the present results suggest the involvement of the dopamine transmission, through D1 and D2/3 receptors of the VTA in the
anxiogenic-like effect of nicotine in the EPM task, we should take into
account the interaction between the VTA and the nucleus accumbens
to the development of nicotine dependence. The nucleus accumbens received dopaminergic neurons from the midbrain VTA which implicated
in motivation and reinforcement. There is also a suggestion that a significant number of nucleus accumbens medium spiny neurons project
back to the VTA (Rahman and McBride, 2001; Xia et al., 2011). Therefore, the observed effect in the present study may be modulated by
the communication of the VTA and the nucleus accumbens.
The elevated plus-maze (EPM) has become one of the most popular
rodent models of anxiety (Carobrez and Bertoglio, 2005; Pellow et al.,
1985) to screen anxioselective effects of drugs (Lister, 1990). Locomotion
capability is important in the EPM test and total arm entries were considered as an index of locomotor activity (Rodgers and Johnson, 1995).
Intra-CeA nicotine injection, at the doses examined, did not change the
locomotion activity of the treated rats. The present result indicates that
the obtained significant differences are not due to locomotion changes.
These results are in agreement with Zarrindast et al. (2008).
5. Conclusion
The results of the present study demonstrate that the anxiogeniclike effect of intra-CeA injection of nicotine may be mediated through
activation of dopamine D1 and D2/3 receptors in the VTA. Such a relationship should be considered in the modulation of anxiety in nicotine effects.
Acknowledgments
The authors thanks the IRAN National Science Foundation (INSF)
for providing the financial support for the project.
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