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Psychopharmacology (2009) 202:589–598DOI 10.1007/s00213-008-1335-0
Naltrexone attenuation of conditioned but not primaryreinforcement of nicotine in rats
Xiu Liu & Matthew I. Palmatier & Anthony R. Caggiula &Alan F. Sved & Eric C. Donny & Maysa Gharib &Sheri Booth
Received: 9 August 2007 / Accepted: 4 September 2008 / Published online: 21 September 2008
administration of naltrexone (0, 0.25, 1, 2 mg/kg). In
Rationale Opioid neurotransmission has been implicated in
separate groups of rats, naltrexone (0, 2 mg/kg) was
reinforcement-related processes for several drugs of abuse,
chronically given before each extinction sessions, where
including opiates, stimulants, and alcohol. However, less is
responses on the active lever resulted in presentations of the
known about its role in the motivational effects of nicotine
CS without nicotine infusion (saline substitution). Self-
and nicotine-associated environmental cues.
administration/naltrexone tests were conducted in different
Objective This study investigated whether pretreatment
groups of rats receiving similar nicotine self-administration
with naltrexone, an opioid receptor antagonist, alters
conditioned incentive salience of nicotine cues under two
Results Naltrexone significantly attenuated the CS-reinstat-
conditions: cue-induced reinstatement of nicotine-seeking
ed responding on the active, previously nicotine-reinforced
after extinction and cue-maintained responding during
lever in the reinstatement tests and the CS-maintained
extinction. The effect of naltrexone on nicotine self-
active lever responding during the extinction tests. In
administration during the maintenance phase was also
contrast, neither acute nor chronic naltrexone produced an
effect on nicotine self-administration behavior.
Materials and methods Male Sprague–Dawley rats were
Conclusions These results indicate that activation of opioid
trained in daily 1-h sessions to self-administer nicotine
receptors is implicated in mediation of the conditioned
(0.03 mg/kg/infusion, i.v.) on a fixed-ratio 5 schedule and
incentive properties of nicotine cues but not in the
associate a conditioned stimulus (CS) with each nicotine
maintenance of nicotine self-administration. Therefore,
delivery. Once responding was extinguished by saline
these findings suggest that opioid receptor antagonists
substitution for nicotine and omission of the CS, the
might have clinical potential for prevention of smoking
reinstatement tests were conducted following subcutaneous
relapse associated with exposure to environmental cues.
Keywords Antagonist . Conditioned stimulus . Extinction .
Division of Neurobiology and Behavior Research,
Naltrexone . Nicotine . Nicotine-seeking behavior .
Department of Psychiatry and Human Behavior,
Opioid receptors . Reinstatement . Self-administration
University of Mississippi Medical Center,2500 N. State St.,Jackson, MS 39216, USAe-mail: [email protected]
X. Liu M. I. Palmatier A. R. Caggiula E. C. Donny
The environmental stimuli associated with administration
M. Gharib S. BoothDepartment of Psychology, University of Pittsburgh,
and subjective effects of nicotine significantly contribute to
the maintenance of and relapse to smoking behavior. Forinstance, clinical studies have demonstrated that smoking
cues produce physiological responses (Abrams et al. ;
Department of Neuroscience, University of Pittsburgh,Pittsburgh, PA 15260, USA
enhance desire to smoke (Drobes and Tiffany
be implicated in mediating rewarding actions and
Droungas et al. Lazev et al. ; McDermut and
dependence of drugs of abuse including nicotine
Haaga ; Perkins et al. ), and increase the rate,
(Gianoulakis Koob and Le Moal ; Maldonado
intensity, and time of smoking (Mucha et al. Surawy
Pomerleau ; Watkins et al. for reviews).
et al. ). Denicotinized cigarettes (i.e., cue) produces
In animal studies, nicotine administration has been found
subjective satisfaction, alleviates withdrawal symptoms,
to increase expression and release of opioid peptides in
and sustains smoking behavior (Butschky et al.
mesolimbic regions (Boyadjieva and Sarkar Houdi
Donny et al. ; Gross et al. Rose et al. ).
Recent animal studies have demonstrated that reintroduc-
Opioid receptor antagonists decrease nicotine-induced
tion of nicotine-associated cues after extinction resulted in
dopamine release in the nucleus accumbens (Tanda and
increased responding on the previously nicotine-reinforced
Di Chiara reduce nicotine reward (Walters et al.
lever (Cohen et al. ; LeSage et al. ; Liu et al.
Zarrindast et al. ), and precipitate withdrawal
symptoms in rats treated chronically with nicotine (Malin
conditioned incentive properties of the nicotine cues.
et al. ). These data suggest the involvement of opioid
Opioid neurotransmission is implicated in response and
neurotransmission in nicotine reinforcement and smoking
adaptation to emotionally salient stimuli in both animal
behavior. However, in the self-administration paradigm,
models and human studies (Filliol et al. Kalin et al.
acute pretreatment with naltrexone or naloxone did not
change operant responding for intravenous nicotine self-
Zubieta et al. It has been proposed that activation of
administration in rats (Corrigall and Coen DeNoble
opioid systems plays a role in mediating conditioned
and Mele Clinical studies in the last three decades
incentive effects of environmental stimuli associated with
have produced inconsistency in the ability of opioid
rewarding actions of drugs of abuse (Benedetti et al.
receptor antagonists to curb smoking (Brauer et al. ;
Zubieta et al. In animal studies, opioid receptor
antagonists have been shown to reverse cue-elicited
Coslett and Griffiths Ray et al. ; Rohsenow et
reinstatement of heroin-seeking behavior (Shaham and
Wong et al. ), and a recent mata-analysis on clinical
recently to reduce reinstatement of responding for oxy-
trial data failed to find the effectiveness of naltrexone on
codone, the most abused prescription opiate (Leri and
smoking cessation (David et al. ). Therefore, it is not
Burns ). Naltrexone, a long-lasting opioid receptor
fully understood whether activation of opioid receptors
antagonist, has been approved by FDA as an anti-
critically contributes to nicotine reinforcement.
alcoholism drug. It effectively decreases alcohol craving
The present study was designed to address two issues.
associated with exposure to alcohol cues in abstinent
First, effect of naltrexone blockade of opioid neurotrans-
alcoholics (Gerrits et al. ; Monti et al. Rohsenow
mission on the conditioned incentive salience of nicotine
et al. ) and reverses reinstatement of ethanol-seeking
cues was investigated under two conditions: cue-reinstated
behavior induced by re-presentation of the ethanol cues in
nicotine-seeking after extinction and cue-maintained nico-
rats (Backstrom and Hyytia ; Bienkowski et al.
tine-seeking during extinction. Second, the effect of not
Burattini et al. Ciccocioppo et al. Dayas et al.
only acute but also chronic naltrexone on nicotine self-
administration during the maintenance phase was also
also attenuates cue-induced reinstatement of methamphet-
amine- and cocaine-seeking behavior in rats (Anggadiredjaet al. ; Burattini et al. ). In nicotine studies, micethat had lower level of expression of opioid receptors in the
ventral tegmental area (Blendy et al. ) and were opioid-deficient by preproenkephalin knock-out (Berrendero et al.
) failed to develop nicotine-induced conditioned placepreference (CPP). Walters et al. (reported that opioid
Male Sprague–Dawley rats (Charles River) weighing 225–
receptor antagonist naloxone blocked expression of nico-
250 g upon arrival were used. Animals were individually
tine-induced CPP. Based on these data, it is hypothesized
housed in a humidity- and temperature-controlled (21–22°C)
that opioid neurotransmission may be implicated in the
vivarium on a reversed light/dark cycle (lights on 19:00 hours,
mediation of conditioned incentive properties of nicotine-
off 07:00 hours) with unlimited access to water. After 1-week
habituation to the vivarium, rats were placed on a food-
Increasing evidence suggests that opioid neurotransmis-
restriction (20 g chow/day) regimen throughout the experi-
sion, together with corticomesolimbic dopamine system, may
ments. Training and experimental sessions were conducted
during the dark phase at the same time each day (09:00–15:00
base) and associate a CS with nicotine delivery. In the
hours). All experimental procedures were carried out in
training sessions, animals were placed in the operant
accordance with the National Institutes of Health Guide for
conditioning chambers and connected to a drug delivery
the Care and Use of Laboratory Animals.
system. The daily 1-h sessions were initiated by introduc-tion of the two levers with illumination of the red house
light. Once the FR requirement on the active lever was met,an infusion of nicotine was dispensed by the drug delivery
Operant training, self-administration, and reinstatement
system in a volume of 0.1 ml in approximately 1 s. Each
tests were conducted in operant conditioning chambers
nicotine infusion was paired with a presentation of the CS
located inside sound-attenuating, ventilated cubicles (Med
consisting of a 5-s tone and illumination of the lever light
Associates, St. Albans, VT, USA). The chambers were
for 20 s. The latter signaled a 20-s timeout period during
equipped with two retractable response levers on one side
which time responses were recorded (included in the total
panel and with a 28-V white light above each lever as well
number of responses) but not reinforced. Responses on the
as a red house light on the top of the chambers. Between
inactive lever had no consequence. An FR1 schedule was
the two levers was a food pellet trough. Intravenous
used for days 1–5, an FR2 for days 6–8, and an FR5 for
nicotine injections were delivered by a drug delivery
remainder of the experiments. All rats received 30 daily
system with a syringe pump (Med Associates, model
self-administration/conditioning sessions.
PHM100—10 rpm). Experimental events and data collec-tion were automatically controlled by an interfaced com-
puter and software (Med Associetes, Med-PC 2.0).
After completion of the self-administration/conditioning
phase, rats were subjected to daily extinction sessions. During the extinction sessions, lever responding was
Rats received food training sessions in order to facilitate
extinguished by withholding nicotine and the CS. Specif-
learning of operant responding for nicotine self-administra-
ically, the daily 1-h extinction sessions began with
tion (see below). In these sessions, responding on the active
introduction of the levers and illumination of the red house
lever was rewarded with delivery of a food pellet (45 mg).
light. Responses on the active lever resulted in the delivery
Sessions lasted 1 h and were repeated until all animals
of saline rather than nicotine, and the CS presentation was
earned 75 food pellets on a fixed-ratio (FR) 1 schedule in a
omitted. The FR5 schedule and 20-s timeout period was
single session. The reinforcement schedule was increased to
still in effect for saline infusions. The criterion for
FR5 and training continued until the same criterion was
extinction was three consecutive sessions, in which the
achieved. Successful food training was achieved within two
number of responses/session was less than 20% of the
to five sessions. During the food training sessions, the
average over the last three self-administration/conditioning
visual/auditory stimulus that later was used as a nicotine
conditioned stimulus (CS, see below) was not presented.
Reinstatement test and effect of naltrexone
One day after the final extinction session, reinstatement
After food training, the rats were anesthetized with isoflurane
tests were conducted under conditions identical to nicotine
and implanted with jugular catheters as described previously
self-administration/conditioning sessions, with the excep-
(Donny et al. The rats were allowed at least 7 days to
tion of saline substitution for nicotine. As such, during the
recover from surgery. For the first 2 weeks after surgery, the
test sessions, responses on the active lever resulted in re-
catheters were flushed twice a day with 0.1 ml of sterile
presentation of the CS and saline infusion (no availability
saline containing heparin (20 units/ml), ticarcillan (14 mg/
of nicotine) on the FR5 schedule with a 20-s timeout
ml), and streptokinase (5 mg/ml) to maintain catheter
period. Thirty minutes before the test sessions, naltrexone
patency and prevent infection. Thereafter, the catheters were
(0, 0.25, 1, 2 mg/kg) was subcutaneously administered to
flushed with the heparinized saline prior to and after the
separate groups of rats (n=12 for each group). Every rat
experimental sessions throughout the experiments.
received only one reinstatement/naltrexone test.
Nicotine self-administration/conditioning
Effect of naltrexone on nicotine cue-maintained responding
After recovery from surgery, rats were trained to intrave-
Two groups of rats (n=12 for each group) were used for
nously self-administer nicotine (0.03 mg/kg/infusion, free
these tests. Animals also received the 30 daily 1-h self-
administration/conditioning training sessions. During the
that were used for the reinstatement/naltrexone tests.
following six daily extinction test sessions, however,
Averaged across the final three sessions (session 28 to
responses on the active lever still resulted in presentation
30), rats made a mean ± SEM number of responses of 83.3
of the CS on the FR5 schedule with saline substitution of
±3.2 on the active lever and 10.8±1.4 on the inactive lever.
nicotine. Thirty minutes before each test sessions, natrex-
Correspondingly, rats earned 15.5±0.6 infusions of nico-
one (2 mg/kg) was subcutaneously administered to one
tine, with a total intake of 1.6±0.1 mg/kg/h. Since rats were
group of rats, with the other group receiving saline
divided into four groups for subsequent reinstatement/
naltrexone tests in a counterbalanced manner, there wasno difference among groups in lever responses. In the first
Effect of naltrexone on nicotine self-administration
extinction session, animals emitted a mean ± SEM numberof responses of 80.8±4.6 on the active lever and 7.8±1.3
Acute test Eleven rats were used to test the effect of acute
on the inactive lever. During subsequent extinction
naltrexone treatment on nicotine self-administration. These
sessions, lever responses gradually decreased. All rats
rats also received the 30 daily self-administration training
reached extinction criterion within ten sessions.
sessions. Then, the naltrexone test sessions began. Naltrex-one (0, 0.25, 1, 2 mg/kg) was subcutaneously administered
Effect of naltrexone on cue-induced reinstatement
30 min before the session in a within-subject design. Every
rat received each dose of naltrexone once in a counter-balanced order. Test sessions were performed every other
A repeated measure ANOVA on the number of active lever
day, with a no-drug pretreatment session in between to
responses revealed a significant main effect of session
eliminate possible carry-over effect of the drug.
[reinstatement vs. extinction (averaged across the final threesessions); F(1,44)=46.50, p<0.0001] and a session × group
Chronic test Two groups of rats (n=8 for each group) were
interaction [F(3,44)=3.00, p<0.05]. Further post hoc
used. The chronic naltrexone treatment tests were con-
analysis showed that in vehicle-treated rats, the number of
ducted after completion of the 30 daily self-administration
active lever responses in the reinstatement test was
training sessions. Thirty minutes before self-administration
significantly higher than that of extinction (p<0.0001),
test sessions, one group of rats received subcutaneous
indicating re-presentation of the CS effectively reinstated
administration of naltrexone (2 mg/kg), and the other group
the extinguished nicotine-seeking behavior. One-way
had saline injection. This self-administration/naltrexone test
ANOVA on the active lever responses during reinstatement
tests yielded significant group (naltrexone dose) effect [F(3,44) =2.89, p<0.05], and subsequent Fisher’s PLSD posthoc test verified significant difference of 2 (p<0.01) and
1 mg/kg (p<0.05) vs. vehicle, indicating that naltrexonedose dependently decreased the cue-induced reinstatement
Data are presented as the mean (±SEM) number of lever
(Fig. , top). However, responses on the inactive lever
responses and nicotine infusions. The data obtained during
remained at low levels indistinguishable from extinction
self-administration and from the reinstatement/naltrexone,
extinction/naltrexone, and the self-administration/acute andchronic naltrexone tests were separately analyzed by using
Effect of naltrexone on cue-maintained responding during
either two- or one-way ANOVA, with repeated measures
wherever appropriate. Subsequently, the Fisher’s PLSDpost hoc tests were used to verify differences among
During the six daily extinction test sessions where active
lever responses resulted in presentations of the CS withoutnicotine (saline substitution), pretreatment of naltrexonesignificantly suppressed the cue-maintained lever respond-
ing. A repeated measure ANOVA on the number of activelever responses revealed a significant main effect of drug
Nicotine self-administration/conditioning and extinction
[naltrexone (n=12) vs. saline (n=12); F(1,22)=26.73, p<0.0001] and session [F(5,110)=25.26, p<0.0001]. Further,
After 30 daily 1-h self-administration/conditioning training
one-way ANOVA showed a significant effect of session in
sessions, rats developed stable levels of operant responding
both naltrexone [F(5,66)=13.22, p<0.0001] and saline
for nicotine delivery administered intravenously. Table
control [F(5,66)=10.66, p<0.0001] groups. In each ses-
shows the profiles of lever responding emitted by the rats
sion, the number of active lever responses in naltrexone-
duringthe self-administration/conditioning
self-administration/conditioning phase as well as
the first used for reinstatement/naltrexone
treated rats was significantly lower than that of saline
showing that nicotine-associated cues effectively reinstated
nicotine-seeking behavior in rats (Cohen et al. ;LeSage et al. Liu et al. ; Liu et al. ;
Effect of acute and chronic naltrexone on nicotine
Paterson et al. ). Importantly, pretreatment with
naltrexone dose dependently attenuated the cue-inducedreinstatement of nicotine-seeking responding in the rein-
One-way ANOVA on the number of active lever responses
statement tests conducted after lever responding was
rats (n=11) emitted during the acute naltrexone test
extinguished. Besides, in the extinction tests performed in
sessions produced no significant dose effect. A repeated
separate groups of rats, naltrexone significantly suppressed
measure ANOVA on the data from chronic tests also failed
the CS-maintained responding, because responses on the
to show significant drug [naltrexone (n=8) vs. saline (n=
active lever resulted in only the CS presentation but not
8)] effect. Therefore, neither acute nor chronic naltrexone
nicotine infusion (saline substitution). These effects could
pretreatment changed nicotine self-administration behavior
not be readily attributable to nonspecific impairment of
general arousal and/or locomotor activity by this agentbecause of the facts that responses on the inactive leverduring the reinstatement tests and responses on the active
lever for nicotine reinforcement during the self-administra-tion tests remained unchanged and that in a recent study,
This study for the first time demonstrates that naltrexone
naltrexone at a dose even higher than that of this study did
blockade of opioid neurotransmission attenuates nicotine
not change cue-induced sucrose-seeking behavior (Burattini
cue-maintained responding during extinction and cue-
et al. ). Therefore, naltrexone produced a selective
induced reinstatement of nicotine-seeking behavior after
suppressant effect on motivational actions of the nicotine
extinction. This finding indicates that activation of opioid
cue. This finding indicates that activation of opioid
receptors may play a role in mediation of the conditioned
receptors may play a role in mediation of conditioned
incentive properties of nicotine-associated cues and sug-
incentive properties of nicotine cues, which underlies the
gests that opioid receptor antagonists, especially naltrexone,
cue-induced reinstatement of nicotine-seeking in animals
would be of clinical potential for prevention of smoking
and relapse of smoking behavior in humans. This argument
relapse triggered by exposure to the environmental smoking
gains support from an observation showing that naloxone,
cues. However, neither acute nor chronic naltrexone
another opioid receptor antagonist, blocked expression of
pretreatment changed nicotine self-administration, suggest-
nicotine-induced CPP (Walters et al. It is also in line
ing that activation of opioid receptors may not be critically
with clinical studies showing that naltrexone decreased
involved in the primary reinforcing effects of nicotine.
smoking cue-induced urge to smoke (Hutchison et al. ;
In the reinstatement tests, response-contingent re-presen-
tation of the CS significantly reinstated extinguished
Increasing animal studies have shown that blockade of
responding on the previously nicotine-reinforced active
opioid neurotransmission attenuates drug cue-induced
lever in rats that received saline vehicle pretreatment,
reinstatement of operant responding for previously self-
indicating conditioned motivational effect of the nicotine-
administered drugs of abuse, including opiates (Leri and
associated cue. It is a replication of previous observation
Extinction Reinstatement Nicotine Infusions Active Lever Responses Naltrexone Dose (mg/kg, SC) Naltrexone Dose (mg/kg, SC) Naltrexone Extinction Reinstatement Nicotine Infusions Naltrexone (2 mg/kg, SC) 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Sessions
Fig. 3 Nicotine infusions earned after acute (top) and chronic (below)
Inactive Lever Responses
data, together with the present finding, suggest that
activation of the opioid receptors may to some extent play
Naltrexone Dose (mg/kg, SC)
a general role in expression of the conditioned incentive
Fig. 1 Effect of naltrexone on lever responses in the reinstatement
properties of environmental stimuli previously associated
tests conducted after extinction. For comparison, extinction responses
with drug taking and subjective effects of the drugs.
averaged across the final three sessions were shown. *p<0.05, **p<
However, it should be noted that naltrexone does not alter
drug priming-elicited reinstatement of cocaine and meth-amphetamine seeking (Anggadiredja et al. Gerrits et
Stewart and Wise ), alcohol (Backstrom and Hyytia
al. operant responding and its associated neuronal
activation under a negative cue condition predictive of the
Ciccocioppo et al. ; Dayas et al. Katner et al.
unavailability of ethanol (Dayas et al. ), and cue-
; Liu and Weiss ), methamphetamine (Anggadir-
induced reinstatement of natural reward sucrose-seeking
edja et al. and cocaine (Burattini et al. ). These
behavior in rats (Burattini et al. These negativeresults further suggest that opioid neurotransmission may
SA (nicotine + CS) Extinction (saline + CS)
be implicated differentially in the associative learning
(Naltrexone, 2 mg/kg, SC)
process involved in addictive drugs vs. natural rewardsand the motivational effects of drug cues vs. drug priming.
Therefore, it is proposed that naltrexone might have a broad
clinical potential for prevention of relapse to drug use,
including cigarette smoking, which is associated with
exposure to environmental drug cues. Active Lever Responses Naltrexone
Animal studies have provided important information on
neuroanatomical substrates for mediation of the conditioned
incentive of the CS and its attenuation by naltrexone. For
Sessions
example, Dayas et al. ), by concomitantly examining
Fig. 2 Effect of chronic naltrexone on nicotine cue-maintained
suppressant effect of naltrexone on cue-induced ethanol
responses. Lever responses made during the last five sessions of the
seeking and expression of immediately early gene c-fos,
self-administration/conditioning training phase were shown for refer-
implicates hippocampus, amygdale, and hypothalamus as
ence. *p<0.05, **p<0.01, ***p<0.001 different from vehicle controlgroup
potential brain regions in mediation of naltrexone attenua-
tion of conditioned ethanol seeking. Gerrits et al. ), by
naltrexone for smoking cessation. To interpret the incon-
using autoradiographic technique, found activation of
sistent clinical results, it has been proposed that opioid
opioid receptors in these brain regions of rats under
response may be only one of the reinforcement mechanisms
conditioned motivational effects of cocaine cues. Studies
for nicotine dependence/smoking and probably that medi-
with human smokers and rats receiving association of
ation of nicotine reinforcement by endogenous opioid
nicotine injection with specific context demonstrated
activity may not be significant in normal smokers under
implication of these brain regions in response to nicotine-
ordinary conditions (Pomerleau ; Sutherland et al.
related cue exposure (Due et al. Schiltz et al.
). In fact, opioid activation may be implicated in
Scott et al. Opioid receptors and its related
nicotine reinforcement mainly under conditions of stress
phosphorylation of the gene transcription factor cAMP
(Pomerleau ). In addition, most clinical studies
response element-binding proteins are required for the
allowed smokers to smoke ad libitum without eliminating
expression of nicotine-induced CPP (Walters et al. ).
the conditioned rewarding aspects of smoking (Robinson et
Based on these data, it is conceivable to propose that these
al. ; Rose et al. ; Rusted et al. so that
brain regions may also be implicated in opioid mediation of
naltrexone possibly interfered with conditioned reward
the motivational effects of the nicotine cues. The role of
rather than primary reinforcement of nicotine. Therefore,
opioid-dependent signal transduction in these neuroanatom-
the results of this study, together with conflicting clinical
ical substrates in mediation of conditioned incentive by
observations on the ability of naltrexone to reduce cigarette
nicotine cues warrants future investigation.
consumption, suggest that clinical trails should focus on the
The second goal of this study was to determine whether
potential of naltrexone for prevention of smoking relapse
naltrexone alters nicotine intake after animal acquired stable
triggered by cue exposure rather than the influence of
level of nicotine self-administration. Parallel to the rats used
nalrexone on reinforcement of nicotine and cigarette
for the cue tests described above, animals for the self-
administration tests also received 30 daily nicotine self-
Another issue that needs to be discussed is the
administration sessions so that they had similar history of
differential effects of naltrexone on conditioned incentive
lever experience and nicotine exposure. The lack of effect
of nicotine cues vs. nicotine self-administration. Increasing
of acute naltrexone pretreatment on lever responding and
data have demonstrated that the conditioned incentive of
nicotine infusions is consistent with previous observations
drug cues and the primary reinforcing actions of the drug
showing that naltrexone and naloxone did not change
may recruit distinct neurocircuitries and thereby show
nicotine self-administration (Corrigall and Coen
different pharmacological profiles. Notably, basolateral
DeNoble and Mele Additionally, taking into consid-
amygdala has been demonstrated to mediate the condi-
eration of the long-term use of this drug in humans, this
tioned but not primary effects of cocaine (Everitt et al.
study also examined whether chronic treatment with
naltrexone would interfere with nicotine intake. Seven
nucleus accumbens neurons have been found to exhibit
daily pre-session administration of naltrexone at its highest
excitation in response to conditioned stimuli but inhibition
dose (2 mg/kg) did not change the number of nicotine
to primary reinforcer (Wilson and Bowman ). Liu and
infusions earned as compared to vehicle control rats.
Weiss ) found that nitric oxide synthesis inhibition
Although this agent may produce differential effects in
attenuated conditioned reinstatement of ethanol seeking, but
nicotine-dependent vs. nicotine-nondependent subjects and
not the primary reinforcing actions of ethanol. Similarly,
the rats used in this daily 1-h self-administration study
Martin-Fardon et al. (demonstrated that antagonism
might not become nicotine dependent (Paterson and
of an orphan sigma (1) receptor reversed cue-induced
Markou these negative results from animal studies
cocaine-seeking but did not change cocaine self-adminis-
mesh with ambiguous clinical observations: Some studies
tration. Even in some cases where one drug produced an
indicated that naltrexone attenuates smoking pleasure and
effect on both the conditioned and primary reinforcement,
cigarette consumption (Epstein and King King and
sensitivity is different. For example, responding motivated
Meyer Sutherland et al. ; Wewers et al. ),
by stimuli conditioned to cocaine is more sensitive to
whereas others failed to show an effect of naltrexone on
glutamate antagonists than behavior maintained by cocaine
smoking reinforcement (Brauer et al. Nemeth-Coslett
itself (Baptista et al. ; Newman and Beardsley
and Griffiths Ray et al. ; Rohsenow et al.
Therefore, it is justifiable to argue that conditioned
Sutherland et al. ; Wong et al. ). A recent mata-
incentive properties of nicotine cues and the primary
analysis of clinical data found no significant difference in
reinforcing actions of nicotine would be mediated to some
quit rates between naltrexone and placebo (David et al.
extent by different neurobiological substrates.
), and the authors recommended that more large-scale
In summary, naltrexone effectively attenuated motiva-
clinical studies are needed to determine the effectiveness of
tional effect of nicotine cues in animal models of drug-
seeking but did not change nicotine self-administration.
comparison in human and mouse. Psychopharmacology (Berl)180:306–315
Considering the fact that although there have been
Boyadjieva NI, Sarkar DK (1997) The secretory response of
pharmacotherapies for smoking cessation such as nicotine
hypothalamic beta-endorphin neurons to acute and chronic
replacement therapies, bupropion, and recently varenicline,
nicotine treatments and following nicotine withdrawal. Life Sci
majority of smokers who try to quit relapse (Aubin et al.
Brauer LH, Behm FM, Westman EC, Patel P, Rose JE (1999)
; Bala et al. ; Gonzales et al. Jorenby et al.
Naltrexone blockade of nicotine effects in cigarette smokers.
; Oncken et al. ); this finding lends support for
continued clinical assessment of the effectiveness of
Burattini C, Gill TM, Aicardi G, Janak PH (2006) The ethanol self-
naltrexone as an adjunctive pharmacotherapy for smoking
administration context as a reinstatement cue: acute effects ofnaltrexone. Neuroscience 139:877–887
cessation but suggests that focus should shift from decrease
Burattini C, Burbassi S, Aicardi G, Cervo L (2008) Effects of
of nicotine intake/cigarette consumption to prevention of
naltrexone on cocaine- and sucrose-seeking behaviour in
smoking relapse associated with exposure to the environ-
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