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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: 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
Nicotine Infusions
Active Lever Responses
Naltrexone Dose (mg/kg, SC)
Naltrexone Dose (mg/kg, SC)
Nicotine Infusions
Naltrexone (2 mg/kg, SC)
26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
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
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.
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