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Roles of the Nucleus Accumbens (Shell) in the Acquisition and Expression of
Morphine‑Induced Conditioned Behavior in Freely Moving Rats
Sara Karimi1,2, Maryam Radahmadi1, Mohammad Fazilati2, Hamid Azizi‑Malekabadi3, Hojjatallah Alaei1
1
Department of Physiology, Isfahan University
of Medical Sciences, Isfahan, Iran, 2Department
of Biology, Faculty of Science, Payame Noor
University, Isfahan, Iran, 3Faculty of Basic Science,
Islamic Azad University, Khorasgan Branch,
Isfahan, Iran
Correspondence to:
Prof. Hojjatallah Alaei,
Department of Physiology,
School of Medicine, Isfahan University
of Medical Sciences, Isfahan, Iran.
E‑mail: alaei@med.mui.ac.ir
Date of Submission: Apr 16, 2013
Original Article
Date of Acceptance: Nov 25, 2013
How to cite this article: Karimi S, Radahmadi M,
Fazilati M, Azizi‑Malekabadi H, Alaei H. Roles of
the nucleus accumbens (shell) in the acquisition and
expression of morphine‑induced conditioned behavior in
freely moving rats. Int J Prev Med 2014;5:262‑8.
ABSTRACT
Background: The nucleus accumbens (NAc) is a part of the
rewarding cortico‑mesolimbic dopamine (DA) pathway. This is a
heterogeneous structure divided in two sub regions termed core
and shell. DA function in the NAc is critical for goal‑oriented
behaviors, including those motivated by drug and brain stimulation
reward. In the conditioned‑place preference (CPP) paradigm, a
test assessing animal’s ability to associate drug‑induced effects
with environmental cause to quantify drug reward for example
morphine.
Methods: In the present study, we investigated the influence
of electrical stimulation with different current intensities on
(25 and 100 µA) with and without an effective dose of morphine
(0.5 and 5 mg/kg) on CPP.
Results: Subcutaneous administration of morphine 5 mg/kg
produced significant CPP in comparison with saline group. Our
findings also showed that electrical stimulation of NAc (100 µA)
significantly (P < 0.01) suppressed morphine‑induced CPP that
reveals impaired learning and memory formation in the process
of conditioning. We found that morphine‑induced CPP can
be successfully suppressed by current intensity (100 µA). It
was probably due to decreasing of dopamine contents and its
metabolites in the NAc. Current intensity (100 µA) in combination
with ineffective dose of morphine (0.5 mg/kg) increased
morphine‑induced CPP probability via the prove reward system.
Conclusions: Since stimulation of dopaminergic neurons increases
tendency to dependence to morphine, therefore in the present study,
the stimulation of the NAc suppressed morphine‑induced CPP
that this shows impairment of learning and memory formation.
Keywords: Conditioned‑place preference, morphine, nucleus
accumbens, rat
INTRODUCTION
In human drug addicts, re‑exposure to a drug of abuse often
induces drug‑seeking behavior and precipitates relapse even after
long‑term periods of abstinence. It has been made clear that the
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Karimi, et al.: Nucleus accumbens and conditioned behavior
administration of opiates increases the craving
for opioids in drug‑free addicts and may reinstate
drug‑seeking behavior after prolonged periods
of extinction in opiate‑experienced animals.[1]
Conditioned‑place preference (CPP) paradigm has
been used widely to study the rewarding effects
of various drugs of abuse, since it involves the
drug‑associated conditioned cue, which may be
responsible for relapse in drug free former addicts.
This property makes the CPP paradigm a useful
tool for testing medications or other approaches
for their effects of anti‑craving and anti‑relapse to
drugs of abuse. Chronic morphine administration
induces functional and morphological alterations in
the mesolimbic dopamine system (MLDS), which
is believed to be the neurobiological substrate of
opiate addiction.[1] Dopaminergic neurons located
in the ventral tegmental area (VTA) and their
anterior projections to the limbic forebrain, for
example, the nucleus accumbens (NAc) and the
frontal cortex.[1]
Evidence for the involvement of the NAc
in reward related mechanisms comes mainly
from 2 types of studies CPP and deep brain
stimulation. Morphine microinjections into the
NAc can produce place conditioning similar to
that after systematically administering morphine.
NAc may play important roles in the formation
of drugs‑context association in CPP paradigm.[2]
In recent years, CPP has been considered as an
efficient method in order to evaluate the extent of
reward caused by drugs. For example, researches
show that morphine and nicotine both can cause
significant and dose dependent CPP.[2] In the
research these effects VTA and accumbens core
have important role. A crucial matter in the
creation of CCP resulting from morphine is the
straight form of these two areas. In addition, some
other areas of the brain are directly involved,
especially award‑dependent ones as memory and
learning areas. It was also emerged that nitric
oxide is effective in gaining and expression of CCP
resulting from morphine.
The NAc can be divided into two major
sub‑regions: The shell ‑ the ventro ‑ medial
part and core the dorsolateral part, which have
different connectivity.[3] The shell sends efferent
projections to the ventromedial ventral pallidum,
extended amygdala ‑ including the bed nucleus of
stria terminalis, central amygdaloid nucleus and
International Journal of Preventive Medicine, Vol 5, No 3, March, 2014
interconnecting sublenticular area., lateral pre‑optic
area, lateral hypothalamus, entopeduncular
nucleus, VTA, mediodorsal substantia nigra pars
compacta, mesopontine reticular formation and
periaqueductal gray. The core sends major efferent
projections to the dorsolateral ventral pallidum,
entopeduncular nucleus, lateral part of VTA and
substantial nigra. There are numerous functions
of NAc, DA in a variety of behavioral such as:
(i) Its role in appetitive behavioral arousal, (ii) its
role as a facilitator as well as an inducer of reward
processes and (iii) role in aversive contexts.[4]
Rewarding properties of addictive drugs are
predominantly attributed to the increasing levels
of synaptic dopamine (DA) in MLDS, including
the VTA and NAc.[5] Chronic administration of
morphine produces a number of adaptive changes
in the MLDS.[1] DA release in terminal regions
in the NAc by inhibiting gamma amino butyric
acid ergic neurons in the VTA, which provide
tonic inhibition of DA neurons, resulting in
increased DA release in terminal regions. Thus
the overwhelming actions of DA in the NAc lead
to neural adaptation that underlies addiction of
drugs.[3] A lot of investigators showed the effect of
electrical or chemical stimulation on different parts
of the brain and its effect on animal’s behaviors,[6]
for example peripheral electrical stimulation (PES)
can suppress both morphine withdrawal syndrome
and morphine‑induced CPP expression in rats,
as well as heroin craving in the addicts. Multiple
100 Hz PES could accelerate the recovery of
morphine‑induced morphological changes of
dopaminergic neurons in the VTA.[1,2] Inhibition
of morphine CPP produced by 100 Hz PES,
suggesting an increased synthesis of dynorphin
in the NAc. This is in line with previous findings
that 100 Hz PES could increase the abundance
of prepro dynorphin messenger ribonucleic in
rat brain.[7] Other investigations showed that
morphine‑induced CPP can be successfully
suppressed by PES, an effect accompanied by a
reversal of the increased tissue contents of DA and
its metabolites in the NAc of morphine‑induced
CPP rats.[7] Chronic high frequency stimulation of
the rat NAc can block CPP induced by morphine
and attenuate morphine reinforcement.[2] In the
study, we used a directional electrical current
for simulation with a freely moving method
of stimulation with least human intervention.
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Karimi, et al.: Nucleus accumbens and conditioned behavior
Therefore, the present study was designed to
evaluate the effect of electrical stimulation with
different current intensities of NAc on effective
and ineffective dose of morphine‑induced CPP.
In the present study, we investigated the influence
of electrical stimulation with different current
intensities on NAc (25 and 100 µA) with and without
an effective dose of morphine (0.5 and 5 mg/kg)
on CPP during conditioning and post‑conditioning
phases.
METHODS
Animals
Male Wistar rats (Pasteur Institute, Tehran, Iran)
weighing 250‑350 g, at the time of surgery, were
used. The animals were kept in an animal house
with a 12‑h light/12‑h dark cycle (light on 6:30)
and controlled temperature (20‑22°C). They had
ad libitum access to food and water. For familiar
animals to laboratory they took to laboratory 2 days
before experiments. Each animal was used once
only. A total of 8 animals were used in each group
of experiments (There are 4 groups and 8 numbers
in each groups). All procedures were carried out in
accordance with institutional guidelines for animal
care and use.
animals were housed individually in Plexiglas
cages immediately after surgery for 72 h and then
they were housed in group of 4 for 5‑6 days prior
to behavioral testing and began to recover from
surgery and the effect of anesthesia.[6]
Apparatus
Apparatus consist of two square base
compartments (height 38 cm × 30 cm × 30 cm):
Two compartment apparatus for conditioned place
preference white and the other with gray walls
(except for the front wall facing the lamp) separated
by a guillotine door to match the respective
wall. The door has to be kept closed during the
conditioning period while it is open during the
pretest and the test.
Behavioral testing
The CPP paradigm took place on 5 consecutive
days by using a biased procedure. The experiment
consisted of the following three phases.[6]
Pre‑test
In the pre‑test investigators estimate the
preference of the experimental animal, for each of
two different environments of CPP apparatus that
can be recognized for visual cues. This estimation
is expressed as the time spent in each environment
while the animal is moving freely between the two.
Conditioning
Drugs
The drugs used in this study were chloral
hydrate (350 mg/kg, intra peritoneal) for anesthetized
and morphine sulfate (Temad, Tehran, Iran)
dissolved in 0.9% saline just before the experiments.
Morphine was injected subcutaneously. Control
animals received vehicle (saline).
In the conditioning phase, the animal is paired
alternately, in one of the two environments
(no preferred one), with the drug under
investigation for its potential motivational effects
or other unconditioned stimulus and in the other
environment, without any specific stimulus.
Number and length of conditioning periods
may vary.
Surgical procedures
The animals were anesthetized with chloral
hydrate (350 mg/kg intra peritoneal) and placed
in a stereotaxic apparatus. A stimulating electrode
was stereotaxically implanted into the NAc of each
animal. Coordinates for the electrode implantation
according to the atlas of Paxinos and Watson were
as follows: Anterio‑posterior, 3. Mediolateral,
1.3 dorsoventral, 6.5 relative to bregma and the
skull surface and were fixed with dental acrylic and
used jewelers screw for the holding of dental acrylic
cements.[8] In this study, we use unipolar stimulation
electrodes and our electrodes were staying during
experiments (near 14 days). Following surgery,
Test
264
Phase after the conditioning, the animal
without any treatment, is tested by placing it in the
apparatus where can freely move between the two
environments. An increase in the time spent in the
environment in which the animal has experienced
the rewarding stimulus is considered CPP.[9]
Experimental design
After recovery from the surgery, animals were
divided into two surgical groups: Morphine‑control
and morphine‑stimulation group. Morphine‑control
group was given effective and ineffective dose
of morphine without any stimulation while
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Karimi, et al.: Nucleus accumbens and conditioned behavior
the morphine‑stimulation group trained with
stimulation before effective and ineffective dose
of morphine injection. The effects of different
electrical current intensities in combination with
ineffective dose of morphine on CPP. In the pilot
study for obtaining optimal current intensity,
each animal was stimulated with two stimulating
current intensities (25, 100, µA) with a constant
stimulation frequency at 25 Hz) just 20 min prior
to morphine administration (0.5 mg/kg) during
the 3‑day conditioning phase and before starting
post‑conditioning phase for 10 min period during
1 s every 5 s (Stimulator Isolator A36O, WPI, USA)
in the separate box which was connected to the
stimulator in the next room.
Effects of different current intensities on NAc in
combination with effective dose of morphine on CPP
In this part of study, four stimulation
current intensities same as the last section
was given to animals just 20 min prior to
morphine administration (5 mg/kg) during the
3‑day conditioning phase and before starting
post‑conditioning phase for 10 min period during
1 s every 5 s. We used these stimulation current
intensities 20 min prior to saline administration in
the next group as the same. Stimulation currents
were adjusted to the intensity at which no motor
side effects were produced (A36O, WPI, USA).
Conditioning score is calculated for each animal
on the test day.
was considered to be statistically significant.
Calculations were performed using SPSS
19 software (SPSS Inc., Chicago, Illinois, USA).
RESULT
Effect of NAc stimulation with 25 µA current
intensity in combination with ineffective doses of
morphine on CPP paradigm
One‑way ANOVA with Tukey test shows that
low current intensity of NAc stimulation causes to
decrease acquisition phase and increase expression
phase of CPP in combination with 0.5 mg/kg dose
of morphine relative to sham group, but this change
not significant [Figure 2a].
Effect of NAc stimulation with 25 µA current
intensity in combination with effective doses of
morphine on CPP paradigm
Statistical analysis of ANOVA with Tukey
test showed that (25 µA) current intensity of
NAc stimulation causes to increase acquisition
phase and decrease expression phase of CPP in
combination with 5 mg/kg dose of morphine
relative to sham group, but this change was not
significant [Figure 2b]. Electrical stimulation of
NAc (25 µA) combination with other doses of
morphine did not significant changes in CPP.
Histology
After completion of behavioral testing, each
animal was sacrificed with an overdose of chloral
hydrate and transcardially perfused with 0.9%
saline, followed by 10% buffered formalin. The
brains were removed and placed in a 10% formalin
for at least 3 days before sectioning. Sections were
examined to determine the location of the electrode
aimed for the NAc. The electrode placements were
verified using the atlas of Paxinos and Watson
[Figure 1]. Data from 3 animals with improper
placements of the electrode in the NAc region
were not used in the analysis.
Statistical analysis
For analyzing data one‑way analysis of
variance (ANOVA) following Tukey’s post‑hoc
test was used. All results were expressed as
mean ± standard error of the mean and difference
with P < 0.05 between experimental groups
International Journal of Preventive Medicine, Vol 5, No 3, March, 2014
Figure 1: The placements of probes implanted in the nucleus
accumbens (NAc) of rats included in statistical analysis,
AcbC; NAc, core: AcbSh; NAc, shell. We compare location
of electrode in NAc (shell) with this form
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Karimi, et al.: Nucleus accumbens and conditioned behavior
Effect of NAc stimulation with 100 µA current
intensity in combination with ineffective doses of
morphine on CPP paradigm
One‑way ANOVA analysis in the acquisition and
expression phase indicated electrical stimulation of
NAc with ineffective dose of morphine causes to
increase in compare with sham group but this change not
significant. Electrical stimulation of NAc (25‑100 µA)
combination with ineffective doses of morphine did
not significant changes in CPP [Figure 3a].
Effect of NAc stimulation with 100 µA current
intensity in combination with effective doses of
morphine on CPP paradigm
Statistical analysis of ANOVA with Tukey
test showed that high current intensity of NAc
stimulation combination with 5 mg/kg dose of
morphine causes to suppress in the acquisition and
expression phase of CPP relative to the sham group
significantly reinforces and causes to aversion. But
this electrical stimulation of NAc before saline
injection had no significant effect.
Our results also showed that NAc electrical
stimulation with current intensity (100 µA) in
combination with 5 mg/kg dose of morphine
causes to aversion and electrical stimulation
(100 µA) in combination with 0.5 mg/Kg dose of
morphine increase in acquisition and expression
a
Effect of different dose of morphine on
conditioned place preference paradigm
ANOVA statistical analysis showed that
different dose of morphine (0.5, 2.5, 5,
7.5 and 10 mg/Kg) increased the time spent in the
drug‑paired compartment compared with saline
compartment. Further Tukey test demonstrated
2.5 mg/kg and 5 mg/kg injection of morphine
increased in time spent in the drug‑paired
compartment compared with that spent in the
saline‑paired compartment (*P < 0.05, ***P < 0.01)
and other doses of morphine had not significant
(P > 0.05) effect on CPP [Figure 4].
DISCUSSION
Drug addiction is primarily characterized by
uncontrollable drug‑seeking behaviors and chronic
drug administration. Drug addiction is also known to
be associated with dysfunction of many brain systems,
including the memory, control and motivational
systems. Brain dysfunction may contribute to the
high rates of relapse in addicted individuals, even
after long periods of abstinence are achieved.[10]
b
Figure 2: (a) Electrical stimulation of nucleus accumbens
(NAc) (25 µA) combination with ineffective doses of
morphine on conditioned‑place preference (CPP) showed
that low dose of morphine with this current intensity increase
expression phase of CPP; (b) Electrical stimulation of
NAc (25 µA) combination with effective doses of morphine
on CPP showed to increase acquisition phase of CPP. The
data were analyzed using one‑way ANOVA followed by
Tukey test P > 0.05
266
phase of CPP relative to sham group thus the
suggest that 0.5 mg/Kg dose of morphine with
combination different current intensity chosen for
subsequent experiments [Figure 3b].
a
b
Figure 3: (a) Electrical stimulation of nucleus accumbens
(NAc) (100 µA) combination with ineffective dose of
morphine increase acquisition and expression phases;
(b) Electrical stimulation of NAc (100 µA) combination
with effective dose of morphine, showed significant effect
NAc electrical stimulation in expression phase of CPP. The
data were analyzed using one‑way ANOVA followed by
Tukey test compared with morphine group **P < 0.01
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Karimi, et al.: Nucleus accumbens and conditioned behavior
Figure 4: Place preference produced by morphine. Doses of
morphine (0.5, 2.5, 5, 7.5 and 10, mg/kg) and saline (1 ml/kg)
were administered in a 3‑day schedule of conditioning. On
the test day, the animals were tested for a 15‑min period.
The change of preference was calculated as the difference
between the time spent on the day of testing and the time
spent on the day of the pre‑conditioning session. Data are
expressed as mean ± standard error of the mean (n = 4‑6).
The data were analyzed using one‑way ANOVA followed
by Tukey test compared with the saline group *P < 0.05;
***P < 0.001
The present study investigated the effects of
electrical stimulation with different current intensities
of NAc on morphine induced‑CPP. The animal
were injected with morphine (0.5 and 5 mg/kg SC)
using an unbiased CPP paradigm. Our findings
showed that the administration of morphine
(2.5 and 5 mg/kg) induced conditioned place
preference [Figure 4]. These findings supported
previous studies demonstrating that administration
of opiates increases the craving for opioids in
drug‑free addicts and may reinstate drug‑seeking
behavior after prolonged periods of extinction in
opiate‑experienced animals.[3,10]
Moreover, in order to obtain the influence
of different currents intensities on NAc, we
used 25 and 100 µA current intensities in combination
with the effective and ineffective doses of morphine
during conditioning and post‑conditioning phases.
These results showed that NAc stimulation with
a high current intensity (100 µA) in combination
with ineffective dose of morphine (0.5 mg/kg)
can induce both acquisition and expression of
morphine‑CPP while NAc stimulation with high
current intensity (100 µA) in combination with
effective dose of morphine (5 mg/kg) could
suppress morphine‑induced CPP [Figure 3b]. In
agreement with these results, previous studies
International Journal of Preventive Medicine, Vol 5, No 3, March, 2014
indicated that PES at 100‑Hz during 30 min a
day for 3 days suppressed both the expression of
morphine‑induced CPP and the reinstatement of
extinguished CPP.[3] Injections of morphine or
amphetamine into the NAc stimulate food intake
therefore feeding stimulation induced by both
drugs is related to their ability to engage reward
systems at the level of the NAc.[11]
The current study showed that high intensity
electrical stimulation of the NAc complete blocks
morphine‑induced CPP. 100 µA current intensity
in combination with 5 mg/kg dose of morphine
can suppress the morphine induced CPP in the
rat [Figure 3b] which may help in reducing the
craving for opiates in drug addicts.[12] Morphine
failed to induce DA increase and was devoid of
rewarding effects evidenced by CPP.[13] Chronic
morphine administration induces functional and
morphological alterations in the MLDS, which is
believed to be the neurobiological substrate of opiate
addiction. Moreover, current present investigation
showed that different doses of morphine
combination with low current intensity (25 µA)
can make different degrees of effect on CPP in
the acquisition and expression phase. In addition,
our results showed that effective or ineffective
electrical stimulation had no significant effect
on ineffective doses of morphine (0.5 mg/kg) in
the expression and acquisition phase [Figure 2a],
but electrical stimulation with high current
intensities (100 µA) combination with 0.5 mg/Kg
dose of morphine can increase in acquisition and
expression phase [Figure 3a]. Therefore, our
suggestion that 100 µA current intensity in
combination with different doses of morphine
examining in a subsequent study because can make
different changes in CPP. Furthermore, electrical
stimulation with low current intensities (25 µA)
combination with 0.5 mg/Kg dose of morphine
produce non‑significant expression phase of
CPP [Figure 2a].
DA in the NAc is critically involved in the
process of reinforcement.[7,14] The mesolimbic
dopaminergic projection from the VTA to the
NAc seems to be of central importance for
reinforcement‑related effects of drug abuse.
Morphine microinjections into the NAc can
produce place conditioning similar to that after
systematically administering morphine. Intra
accumbens injections of the DA receptor antagonist
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Karimi, et al.: Nucleus accumbens and conditioned behavior
or lesion of the NAc decrease the reinforcing
effect of drug abuse. In support of this, lesion this
pathway or blocking dopaminergic transmission
in the NAc would attenuate the reinforcing effect
of drugs.[14] Hence, it is possible that activation
of mesolimbic DA system is critically related to
link to the expression of morphine‑induced place
preference in mice.[2]
5.
6.
CONCLUSIONS
Our results revealed that electrical stimulation
of NAc with high current intensities in combination
with 5 mg/Kg dose of morphine blocked morphine
induced‑CPP which is due to disruption in CPP
process. In contrast, using high current intensities
in combination with 0.5 mg/Kg dose of morphine
cause the increase in the expression and acquisition
phase of CPP. It is possible that stimulation of NAc
with 100 µA leads to activate the reward system
and produce pleasure, like the effect of morphine.
7.
8.
9.
10.
ACKNOWLEDGMENTS
This research was supported by Isfahan University
of Medical Sciences, Isfahan, Iran.
11.
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Source of Support: This research was supported by
Isfahan University of Medical Sciences, Isfahan, Iran,
Conflict of Interest: None declared.
International Journal of Preventive Medicine, Vol 5, No 3, March, 2014