Original Article
Submitted: 22 Sep 2014
Accepted: 23 Jan 2015
Effects of Temporary Inactivation and
Electrical Stimulation of the Dorsal
Raphe Nucleus on Morphine-induced
Conditioned Place Preference
Gholam Reza Ghavipanjeh1, Ali Asghar pourshanazari1,
Hojjatllah alaei1, Sara Karimi2, Meghdad Abarghouei nejad2
1
Department of Physiology, Faculty of Medicine, Isfahan University of
Medical Sciences, Isfahan, Iran, postal code: 81746-73461
2
Department of Physiology, Faculty of Sciences, Payamnoor Isfahan
University, Isfahan, Iran, postal code: 81395-671
Abstract
Background: The dorsal raphe nucleus (DRN) influences a wide range of behavioral and
reward function. In this study, we evaluated electrical stimulation and inactivation of DRN on
morphine conditioned place preference (CPP).
Methods: The rats were anesthetised (n = 7 for each group) and the electrode and cannula
were implanted into the DRN by stereotaxic instrument. Electrical stimulation (100µA) and reversible
inactivation by lidocaine were induced into DRN and then morphine-induced CPP was investigated.
Results: The stimulation of DRN in combination with effective dose of morphine showed a
significant decrease only on expression phases 20s (SD 33.7) when compared with morphine group
119.85s (SD 23.7) (One way ANOVA, Tukey’s; P = 0.036). Also, this stimulation in combination with
ineffective dose of morphine showed a significant increase only on acquisition phases 67.5s (SD 41.2)
of CPP compared with morphine group -46s (SD 18.51) (P = 0.034). Also, there were not significant
differences in inactivation of DRN by lidocaine on different phase of CPP (P = 0.091).
Conclusion: It is possible that electrical stimulation of the DRN with changes in concentration
of serotonin or involving other transmitters such as glutamate and gamma amino butyric acid
(GABA) would be involved to these changes of CPP.
Keywords: conditioned place, electrical stimulation, morphine, dorsal raphe nucleus, Lidocaine, rat
Introduction
It has been shown that dorsal raphe nucleus
(DRN) has an important role to control and
modulate many behaviors (1). Reported that
serotonin releases from this nucleus which is
related to reward behaviors (1–3), as well as other
functions, for example the rhythm of sleep–wake
(4,5), appetite (6), locomotion (7), emotion and
social behavior (8,9) and learning and memory
(10). Nevertheless, the mechanism of the serotonin
system in the cognitive and motivational behavior
has not been cleared yet. Electrophysiological
investigations of the raphe nuclei have been
concentrated mostly on motor behavior and
rhythm of sleep–wake (10). Moreover, some
evidence report that decrease in serotonergic
neurotransmission involves independency and
opioid tolerance (11). Opioids are produced
endogenously and their receptors are recognized
in the periaqueductal gray matter and the DRN
(12). Opioids enhance extracellular serotonin in
some area in the brain which are innervated by
the DRN (13). According to previous report acute
morphine administration increased serotonin
turnover in the mammalian brain, but the
increase in turnover was attenuated after chronic
morphine administration (11). In addition, it
has been shown that the 5-hydroxytryptamine
(5-HT) is involved in the mechanisms, related
to the withdrawal syndrome behavior associated
with naloxone induced withdrawal in rat (14).
Some evidence report that a selective lesion of
5-HT neurotransmissions in the dorsal raphe
nucleus does not modify affective behavior but
instead, 5-HT seem to control the activities
associated to the creation of object memory (15).
Other studies showed that the lesion of the
DRN has no effect on passive avoidance retention
(16). There is no document to show the role of
the DRN in different phase of conditioned place
preference (CPP). The CPP has developed as a
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routine experimental protocol to measure the
rewarding consequences of drug abuse (17,18).
Various rewards, as sweetened solutions,
drugs abused and eating pleasant foodstuff
by humans, electrical brain stimulation, have
been demonstrated to induce CPP (19). Using
of opioid in other animals such as rabbits and
monkeys should be induced CPP (18,20,21).
Administration of opiates, similar other drug
abuse, will induce inclinations for conditioning
of separate environments (22). Previous studies
are indicated that pharmacological inhibition and
electrolytic lesions of the DRN prevent stressor
potentiation of morphine CPP in rats (23). In
addition, withdrawal of syndrome signs were
decreased by application of electrical stimulation
in DRN, in comparison with morphine groups
(14). The goal of this study was to investigate
the effect of electrical stimulation (100 μA) and
reversible inactivation by lidocaine on DRN in
combination with effective and non-effective doses
of morphine (2.5 and 0.5 mg/kg) respectively on
different phase of morphine-induced CPP were
investigated.
injection needle (30 G) which was related to the
Hamilton syringe through a short polyethylene
tube in the cannula was placed. Then 0.5 µL of
2% lidocaine hydrochloride (Bayer) was injected
for 60 sec (25).
Materials and Methods
Pre-test
In the pre-test (day 1) each rat is placed in
C chamber while the middle door was open and
the rat is allowed to move freely for 15 minutes
in all chambers. The time spent in each chamber
(A and B) was recorded by the apparatus.
Animals
Wistar rats with male gender (Isfahan
University, Isfahan, Iran) weighing 200–250 g,
were used in this study. Rats were maintained
in animal house at 12 h light – 12 h dark normal
cycle with water and food available at all times.
The laboratory temperature was maintained at
22–25 °C. For at least 10 days prior to surgery,
all rats were allowed to adapt to the laboratory
environment. In each group of experiments seven
rats were used.
Surgery
All rats were anesthetised with chloral hydrate
injected intraperitoneally (400 mg/kg) and after
shaving their heads were located in a stereotaxic
instrument, then were implanted a cannula
(22 G) or stimulating electrode into the DRN.
Coordinates of the point is (AP) –7.92 mm; (ML)
0.2 mm; (DV) 6.4 mm relative to bregmae (24).
Finally, the cannula and stimulating electrode
were anchored to the skull by dental cement. In
order to protect from infection, Penicillin (0.2
ml i.p) was administered immediately after the
surgery. Subsequent surgery, each rat was alone
kept in animal house for 72 h.
Micro injection method
Initially, the rats were kept in hand and the
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Drugs
During the experiment, morphine sulfate
daily by dissolving in saline 0.9% are prepared for
injection (subcutaneously).
Apparatus
The CPP apparatus consisted of three
chambers (A, B, and C). Two chambers (A and
B) are the same size but in different colors. The
walls and floor of the A chamber is a black and
white while the walls and floor of the B chamber
is white. The C chamber was smaller and by
Guillotine door is connected to A and B chambers.
Behavioral procedure
The Behavioral procedure of CPP is done on
five continuous days and has three distinct phases
(22–26,27).
Conditioning
This phase consisted of 3 days (from day 2
to day 4). This stage consisted of six sessions
(3 saline and 3 morphine) and each session
lasts 45 minutes. Guillotine door is closed and
daily injection is performed in two stages with a
6 h interval. In this case, in the morning of the
second day (8 am) after subcutaneous injection of
morphine, rats were confined to one chamber of
the apparatus for 45 minutes. In the evening with
an interval of 6 h (2 pm) after injection of saline
instead of morphine rats were confined to in other
side of the apparatus for 45 minutes. On the day
3, morphine, and saline injections were contrary
to the day 2. On the day 4, morphine and saline
injection were same as the day 2 (22–26).
Test
This phase includes the day 5. At this phase
Guillotine door is open as the first day and the
rats can freely move in all chambers for 15
minutes and the spent of time in the chamber of
rats received morphine are recorded. The several
of preference were computed as the difference
Original Article | Dorsal raphe nucleus and morphine-induced CPP
(in second) between the times spent in morphine
receiving chamber on the test day and the first
day.
Experimental design
One week after surgery, rats were randomly
assigned to 15 groups (n = 7 in each) as follows:
1. Group 1: Saline
2. Group 2: Saline+ stimulation (100 μA;
Acquisition)
3. Group 3: Saline+ stimulation (100 μA;
Expression)
4. Group 4: Saline+ Lidocaine (0.5 μL;
Acquisition)
5. Group 5: Saline+ Lidocaine (0.5 μL;
Expression)
6. Group 6: Morphine (0.5 mg/kg, Sc)
7. Group 7: Morphine (2.5 mg/kg, Sc)
8. Group 8: Morphine+ Stimulation (0.5
mg/kg+ Sc+ 100 μA; Acquisition)
9. Group 9: Morphine+ Stimulation (0.5
mg/kg+ Sc+ 100 μA; Expression)
10. Group 10: Morphine+ Stimulation (2.5
mg/kg+ Sc+ 100 μA; Acquisition)
11. Group 11: Morphine+ Stimulation (2.5
mg/kg+ Sc+ 100 μA; Expression)
12. Group 12: Morphine+ Lidocaine (0.5
mg/kg+ Sc+ 0.5 μL; Acquisition)
13. Group 13: Morphine+ Lidocaine (0.5
mg/kg+ Sc+ 0.5 μL; Expression)
14. Group 14: Morphine+ Lidocaine (2.5
mg/kg+ Sc+ 0.5 μL; Acquisition)
15. Group 15: Morphine+ Lidocaine (2.5
mg/kg+ Sc+ 0.5 μL; Expression)
Determine effect and non-effect dose of morphine
In order to determine effective and noneffective dose of morphine, different doses (0.5,
2.5, 5, 7.5, and 10 mg/kg) were used. Saline and
morphine were injected (Sc) during 3 days of
conditioning phase and the spent of time in the
morphine chamber on day 5 minus that the spent
of time in this chamber in the day 1 was computed
to assess induced of CPP.
The method of electrical stimulation
To electrical stimulation, the current intensity
(100 µA) with a constant frequency of (25 Hz)
was used (22). Each animal was stimulated for 10
minutes (Stimulator Isolator A36O, WPI, USA)
and morphine (effective and ineffective doses)
was administered after 15 minutes (22). Electrical
stimulation for the acquisition group during the
conditioning stage and for expression group
during the test stage was applied.
Histology
At the end of experiments, the rats were
sacrificed and with 0.9% saline followed by 10%
formalin were perfused and their brains were
removed carefully then before slices were placed
in 10% formalin for 72 hours. In order to evaluate
the place of the stimulating electrode and cannula
in the DRN, sections were examined (Figure 1)
(24).
Statistical analysis
All results are indicated as mean (SD). In
order to analyse data, one - way ANOVA following
Tukey post-test was used. Calculations were
performed using the SPSS statistical software 21.
Results
The results showed that there was a
significant (One way ANOVA, Tukey’s: P =
0.006) enhancement only in dose of (2.5 mg/kg)
of morphine 178.4 s (SD 18.4) comparative with
control group 57.1 s (SD 8.8). Therefore, in this
study 0.5 mg/kg of morphine as ineffective dose
and 2.5 mg/kg of morphine as effective dose was
used. The results demonstrated that morphine
response on CPP was not dose dependent (Figure
2). The stimulation of the DRN (current intensity;
100µA) with effective dose of morphine did
not show significant differences on acquisition
phase (P = 0.250) whereas there was significant
decrease 20 s (SD 33.7) on expression phase
compared to morphine group 119.85 s (SD 23.7)
Figure 1: Location of electrode (a) and cannula
(b) in the DRN of rats used in the
stimulation studies and reversible
inactivation after using lidocaine. The
location of stimulating electrodes and
cannula in the DRN are shown by
arrows.
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Malays J Med Sci. Mar-Apr 2015; 22(2): 33-40
(P = 0.036) on CPP paradigm (Figure 2 and
4). Also this current intensity (100 µA) with
ineffective dose of morphine showed a significant
increase on acquisition phase 67.5 s (SD 41.2)
of CPP compared to morphine group –46 s (SD
18.51) (P = 0.034) but did not show significant
differences on expression phase (P = 0.280)
compared to morphine group on CPP paradigm
Figure 2: The effects of various doses of
morphine administration on CPP
for determining the effect and noneffect doses of morphine, (One
way ANOVA, Tukey’s: *P = 0.034)
comparative with the saline group.
Figure 3: Electrical stimulation with current
intensity (100 μA) of dorsal raphe
nucleus with effect and non-effect
doses of morphine on acquisition of
conditioned place preference, (One
way ANOVA, Tukey’s: *P = 0.041)
comparative with the morphine
group.
Abbreviation: mor = morphine; st =
stimulation; sal = saline.
Figure 4: Electrical stimulation with current
intensity (100 μA) of dorsal raphe
nucleus with effect and non-effect
doses of morphine on expression of
conditioned place preference, (One
way ANOVA, Tukey’s: *P = 0.036)
Comparative with the morphine
group.
Abbreviation: mor = morphine; st =
stimulation; sal = saline.
Figure 5: Reversible inactivation of DRN by
lidocaine with effect and non-effect
doses of morphine on acquisition of
conditioned place preference, (One
way ANOVA, Tukey’s: *P = 0.032)
comparative with the morphine
group and (One way ANOVA,
Tukey’s: #P = 0.043) comparative
with the mor+lidocaine group.
Abbreviation: mor = morphine; sal =
saline.
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Original Article | Dorsal raphe nucleus and morphine-induced CPP
(Figure 3 and 4). In addition results indicated
that there was not significant differences (P =
0.091) in reversible inactivation of the DRN after
using lidocaine on different phases of CPP by
effect and non-effect dose of morphine compared
to morphine group on CPP paradigm but there
was significant differences on acquisition phase in
sal + lidocaine group 54.6 s (SD 35) compared to
morphine group –46 s (SD 18.51) on CPP (*P =
0.046) and Comparative with the mor+lidocaine
group –31.3 s (SD 3.02) (#P = 0.035) (Figure 5
and 6).
Our data also indicated that electrical
stimulation and reversible inactivation of DRN
did not have a significant effect (P = 0.250) on
the locomotors activities (Figure 7 and 8).
Discussion
Figure 6: Reversible inactivation of DRN by
lidocaine with effect and non-effect
doses of morphine on expression of
conditioned place preference, (One
way ANOVA, Tukey’s: P = 0.250).
Abbreviation: mor = morphine; sal =
saline.
Morphine is one of the most frequently
used pain-relieving drugs to acute pains, but
the euphoria effect of this opioid produce a
difficulty in therapeutic strategies as drug abuse
(21,28). On the other hand, CPP has become one
of the acceptable animal models to evaluate the
rewarding properties of drug abuse and other
neurotransmitters (17,18). Our results showed
that there was a significant enhancement only
in dose of (2.5 mg/kg) comparative with control
group. There were significant differences on
expression phases compared to morphine group
on CPP paradigm. Also, this current intensity
(100 μA) with ineffective dose of morphine
showed different responses on acquisition phases
of CPP.
Several researches have showed the
mechanism of neurobiology on rewarding
properties of opiate using the Conditioned Place
Preference model, somewhat fewer investigation
has been done to examine the effects of the DRN
stimulation or lesion on morphine-induced CPP.
Figure 7: The effect of electrical activation and
reversible inactivation of DRN with
effective doses of morphine on motor
activity in CPP (One way ANOVA,
Tukey’s: P = 0.074).
Abbreviation: mor = morphine; st
= stimulation; sal = saline; aq =
acquisition; ex = expression.
Figure 8: The effect of electrical activation and
reversible inactivation of DRN with
non-effective doses of morphine on
motor activity CPP (One way ANOVA,
Tukey’s: P = 0.092).
Abbreviation: mor = morphine; st
= stimulation; sal = saline; aq =
acquisition; ex = expression.
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Malays J Med Sci. Mar-Apr 2015; 22(2): 33-40
Drug addiction is also known to be associated
with dysfunction of motivational systems and
memory in rats (29). Some of the investigators
indicated the effect of chemical stimulation or
electrical on different sites of the central nervous
system and its influence on animal’s behaviors
(30,31). Data showed the administration of opiate
induced CPP (18,20,21). In addition, morphineinduced CPP was not dose dependent (Figure 2).
Several studies demonstrated that administration
of opiates raises the desire for opioid in drug-free
addicts and may restore drug seeking actions after
long periods of extinction in opiate-experienced
animals (29,32). Consistent with these behavioral
data, other studies demonstrated morphine
induced pleasure, which is associated to the
location where in these actions happened (27,33).
Our results indicated that the stimulation of the
DRN with high current intensity (100 μA) in
grouping with non-effect dose of morphine can
induce acquisition phase of CPP by morphine
(Figure 2 and 4), while high current intensity the
DRN stimulation (100 μA) in grouping with affect
dose of morphine could destroy CPP induced
by morphine (Figure 3). It demonstrated that
there were not significant differences in the DRN
reversible inactivation after injection of lidocaine
in different phase of CPP by effect of morphine
on CPP paradigm (Figure 2, 3, and 4). Since, our
data indicated that electrical activation of the
DRN with intensity 100 µA reinforces ineffective
induced CPP by morphine. This consequence may
be because of an enhancement in the affect signal
or adequate reaction to the rewarding stimuli,
which memory forms and reinforces learning
in the conditioning procedure. It is notable that
the DRN projects to areas involved in facilitating
drug reward such as the medial prefrontal cortex
and the shell of the nucleus accumbens (23). In
addition, it has been reported that, increase in
5-HT above normal levels within the medial
prefrontal cortex and nucleus accumbens increase
dopamine efflux in these areas (34). On the other
hand, it is reported that the serotonin neuronal
part of dorsal raphe nucleus could control
the ventral tegmental area (VTA) a dopamine
(DA) projection to the NAc (35). Electrical
stimulation also leads to an increase in dopamine
neurotransmission (36). So it is possible that the
DRN electrical stimulation resulted in elevation
levels of serotonin in the nucleus accumbens,
followed the release of dopamine, is increased
and will lead to increase memory formation
and reinforce learning. Electrical activation of
the DRN with high intensities may increase
morphine-induced CPP due to increasing the
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craving for opiates in drug addicts. Conversely
our data revealed that electrical stimulation of
the DRN with high intensity blocks effective
induced CPP by morphine in expression phase.
It may be due to a decrease in the insufficient
response to the rewarding stimulator reward
signal, which damage memory formation and
learning in the conditioning procedure. Therefore
learning insufficiency, that damages conditioning
procedure, might be destroy induced CPP by
morphine (31). Parallel to these findings, it
was proposed that chronic high-frequency
stimulation suppress morphine reinforcement
(37). Furthermore, some of the researches
obtained different results after special effects of
electrical activation on CPP (27,37). In harmony
with these data, other investigates indicated that
peripheral electrical activation suppressed both
the reinstatement of extinguished CPP and the
expression of CPP induced by morphine (32).
Conclusion
In summary according to the role of the DRN
in learning and memory it is possible that electrical
stimulation of this nucleus leads to reduction in
the reward signal or inadequate response to the
rewarding stimuli, which impair learning and
memory formation in the conditioning process, is
responsible for these changes in CPP.
Acknowledgment
The authors would like to thank Dr Ali Nasimi
and Dr Maryam Radahmadi for their valuable
assistance. Conduction of the present research
was made possible through the supports received
from Isfahan University of Medical Sciences,
Isfahan, Iran.
Conflict of Interest
None.
Funds
I confirm that I have mentioned all organisations
that funded my research in the acknowledgements
section of my submission where appropriate.
Authors’ Contributions
Conception and design, critical revision of the
article for the important intellectual content:
AAP, HA
Drafting of the article: GRG, AAP, HA
Original Article | Dorsal raphe nucleus and morphine-induced CPP
Administrative, technical or logistic support:
GRG, SK, MAN
Collection and assembly of data: GRG
Correspondence
Dr Ali asghar Pourshanazari
PhD (Isfahan University of Medical Sciences)
Department of Physiology
Faculty of Medicine
Isfahan University
Hezar Jerib St. Isfahan
81746-73461
Iran
Tel: +0098-917 131 3902
Fax: +0098-313 668 8597
Email: poursha@med.mui.ac.ir
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