Assessing learned associations between conditioned cocaine reward and environmental stimuli in the Wistar Kyoto rat

Clinical studies demonstrate that anxiety disorders increase the risk of substance use disorder. However, few studies have directly assessed anxiety as a vulnerability factor in processing of rewarding stimuli. The Wistar-Kyoto (WKY) rat has been proposed as a model of anxiety vulnerability because it exhibits extreme behavioral inhibition in novel and social environments; yet, it displays paradoxical rapid active avoidance learning that is resistant to extinction. The present study was designed to characterize the acquisition and persistence of cocaine conditioned place preference (CPP) in WKY rats. In the first of a series of three experiments, adult male WKY and Sprague Dawley (SD) rats were given six pairings of cocaine (3, 5, 10, 15 mg/kg) or saline on alternating days. SD rats developed cocaine-induced CPP to each of the four doses of cocaine tested. In contrast, WKY rats demonstrated CPP when conditioned with 3, 5, and 10 mg/kg, but displayed no preference to the 15 mg/kg dose. Next, separate groups of rats were subject to an extended CPP paradigm, which included acquisition, extinction and reinstatement phases. Rats were conditioned with cocaine and saline on alternating days using either a 6/6 (as above) or 4/4 conditioning regimen. Both SD and WKY rats acquired a lasting CPP with the 6/6 conditioning regimen. Results from the 4/4 conditioning regimen show that SD, but not WKY, rats acquired CPP. Preference scores for SD rats during the cocaine primed reinstatement test were significantly different from pretest scores indicating reinstatement of CPP in this group. Paradoxically, WKY rats demonstrated a latent sensitization to the conditioned rewarding effects of cocaine during the drug-primed reinstatement test. Taken together, WKY rats appear to be more sensitive to high doses of cocaine and need more experience with the drug to acquire a preference than SD rats.     

Memantine and ACPC affect conditioned place preference induced by cocaine in rats

The influence of uncompetitive NMDA receptor antagonist, 1-amino-3,5--dimethyl-adamantane (memantine) and partial glycineB site agonist, 1-amino-cyclopropanecarboxylic acid (ACPC) on cocaine-induced conditioned place preference (CPP) were examined in male Wistar rats. After determination of initial preference, animals were conditioned with cocaine (5 mg/kg, ip) for 3 conditioning trials, alone or in combination with memantine (7.5 mg/kg, ip) or ACPC (50.0 mg/kg, ip). Memantine prevented acquisition and expression of the place preference produced by cocaine, while ACPC prevented only acquisition effect. Neither of the NMDA antagonists displayed any reinforcing properties by itself. Our current data suggest that the NMDA receptor complex may be involved in the rewarding effect of cocaine.     

Stimulation of serotonin1B receptors induces conditioned place aversion and facilitates cocaine place conditioning in rats

RATIONALE: Changes in serotonin(1B) (5-HT(1B)) receptor function appear to modify the reinforcing properties of cocaine, but the direction of this effect is not completely clear. Pharmacological stimulation of 5-HT(1B) enhanced the rewarding properties of self-administered cocaine while attenuating the threshold-reducing effect of cocaine in the intracerebral brain stimulation procedure. OBJECTIVE: The present study investigates how pharmacological modification of 5-HT(1B) receptor-mediated neurotransmission influence cocaine motivational properties in the conditioned place preference paradigm in rats. METHODS: In separate groups of rats the motivational properties of CP 94,253, a selective 5-HT(1B) agonist, or GR 127935, a 5-HT(1B/D) receptor partial agonist, given alone or in combination, were determined. To evaluate their influence on cocaine-induced place conditioning, CP 94,253, that was found to be aversive, was given every day before each conditioning session, while GR 127935, which given alone had no effect, was administered only before cocaine conditioning sessions. RESULTS: CP 94,253, injected IP at 2.5 and 10 (but not 0.5) mg/kg produced place aversion in the place conditioning paradigm. The aversive effect of 2.5 mg/kg CP 94,253 was completely reversed by 10 mg/kg SC GR 127935. Given before every conditioning session, CP 94,253 did not modify place conditioning by four injections of 10 mg/kg cocaine but at 2.5 mg/kg it potentiated a sub-threshold dose of cocaine. The place preference caused by these two drugs was completely reversed by 10 mg/kg GR 127935. The antagonism by GR 127935 of CP 94,253's effects was shown not to be due to the induction of state-dependent effects. CONCLUSION: The results suggest that stimulation of 5-HT(1B) receptors causes place aversion, and enhances the effect of low doses of cocaine in the conditioned place preference paradigm.     

Effects of the NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced place preference.

Effects of the novel NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced conditioned place preference (CPP) were examined in male Wistar rats. After determination of initial preference, animals were conditioned with morphine (5 mg/kg, i.p.) or cocaine (5 mg/kg, i.p.) for 3 conditioning trials, alone or in combination of these drugs with L-701,324 (2.5 mg/kg and 5 mg/kg, p.o.). L-701,324 prevented acquisition of the place preference produced by morphine and cocaine. Administration of L-701,324 on the test day attenuated the expression of morphine-induced CPP, whereas it had no effect on cocaine CPP. When L-701,324 was given alone it did not affect dependent variables (i.e. time spent in non-preferred compartment) suggesting that L-701,324 did not display any reinforcing properties by itself. Our current data suggest that glycine site on the NMDA receptor complex may be involved in the mediation of the rewarding effects of drugs of abuse.     

Absence of cocaine-induced place conditioning in serotonin 1B receptor knock-out mice

A large body of evidence suggests that genetic factors may affect the reinforcing properties of drugs of abuse. This study investigated the involvement of the serotonin 1B (5-HT1B) receptor in modulating cocaine-induced place conditioning by comparing the response of 5-HT1B receptor gene knock-out mice with wild type 129/Sv-ter mice. The rewarding effects of various doses of cocaine (0, 2.5, 5, 10, 20, and 40 mg/kg) were examined in both strains. Results clearly show that 5-HT1B receptor knock-out mice failed to display a conditioned place preference for stimuli paired with cocaine while wild type mice exhibited a conditioned place preference for the compartment paired with cocaine (5 and 20 mg/kg). As other studies showed that 5-HT1B knock-out mice self-administer cocaine, these results suggest a dissociation between the psychologic state linked to self-administration and the one measured in conditioned place preference.     

Cross-reinstatement by cocaine and amphetamine of morphine-induced place preference in mice

The cross-reinstatement by psychostimulants of a conditioned place preference (CPP) induced by morphine was evaluated in mice. In Experiment 1, we examined the effects of a single dose of cocaine and amphetamine on a previously extinguished morphine CPP. After acquisition of CPP induced by morphine (40 mg/kg), animals underwent daily extinction sessions of 15 min duration until the CPP was extinguished. Subsequently, animals received a non-contingent injection of cocaine (25 mg/kg) or amphetamine (4 mg/kg), which produced the reinstatement of the extinguished morphine-induced CPP. In Experiment 2, we evaluated the reinstating effects of several priming doses of cocaine (Experiment 2A) or amphetamine (Experiment 2B). As in the first experiment, after conditioning with morphine (40 mg/kg), mice underwent daily 15 min extinction sessions. When the preference was no longer evident, we tested the effects of cocaine (0, 6.25, 12.5, 25 and 50 mg/kg) and amphetamine (0, 0.5, 1, 2 and 4 mg/kg) on the reinstatement of CPP. Doses from 12.5 mg/kg of cocaine upward and doses from 1 mg/kg of amphetamine upward effectively reinstated CPP. Our results demonstrate cross-reinstatement with psychostimulants and opiates, suggesting that in abstinent individuals, drug exposure can produce craving for the previously abused drug and relapse.     

Expression of cocaine-induced conditioned place preference in apomorphine susceptible and unsusceptible rats

Differences in cocaine self-administration can be attributed to differences in the rewarding value that cocaine has for the individual. An ongoing debate, however, exists whether a high rewarding or a low rewarding value leads to an increase in self-administration. To investigate which of these two alternatives is correct, we investigated the occurrence of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats. We have recently shown that under specific environmental conditions (challenged-not habituated to the environment-as measured by distance travelled) apomorphine susceptible rats consistently self-administer more cocaine than apomorphine unsusceptible rats do. As conditioned place preference allows the assessment of the rewarding value of cocaine, we investigated the expression of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats under the same conditions as the self-administration experiments in order to establish whether the rewarding value of cocaine is greater or smaller in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats. The data clearly showed that challenged apomorphine susceptible rats had a preference for the cocaine-paired compartment with lower doses of cocaine (10 mg/kg) than challenged apomorphine unsusceptible rats. Apomorphine unsusceptible rats expressed conditioned place preference only with the highest dose tested (20 mg/kg). On the basis of these data, we concluded that the rewarding value that cocaine has in challenged apomorphine susceptible rats is greater than that in challenged apomorphine unsusceptible rats. It is suggested that challenged apomorphine susceptible rats self-administer more of a lower dose of cocaine than challenged apomorphine unsusceptible rats do, because the rewarding value of cocaine is greater in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats.     

Effects of a newly synthesized κ-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats

RATIONALE: We previously demonstrated that the prototypical kappa-opioid receptor agonist U-50,488H did not affect the discriminative stimulus effects of cocaine, and the dose of U-50,488H which significantly induced aversive effects attenuated the rewarding effects of cocaine. OBJECTIVES: In the present study, the effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine were examined in rats. METHODS: In the drug discrimination procedure, the effects of TRK-820 on the discriminative stimulus effects of cocaine were examined in rats that had been trained to discriminate between 10 mg/kg cocaine and saline. TRK-820-induced place preference or place aversion and the effects of TRK-820 on the cocaine (4 mg/kg)-induced place preference were examined using a conditioned place preference procedure in rats. RESULTS: TRK-820 did not engender cocaine-like responding in rats trained to discriminate between 10 mg/kg cocaine and saline. In combination tests, low doses of TRK-820, which did not affect the response rate, significantly attenuated the discriminative stimulus effects of cocaine, and these effects of TRK-820 were reversed by a kappa-opioid receptor antagonist, nor-BNI. In the conditioned place preference procedure, low doses of TRK-820, which did not affect the response rate in the drug discrimination, did not produce either place preference or place aversion, whereas, higher dose (80 microg/kg) of TRK-820 slightly but significantly induced a place aversion. Under these conditions, the cocaine-induced place preference was completely attenuated by low doses of TRK-820. These results may prompt further investigation of the effectiveness of the new kappa-opioid receptor agonist TRK-820 as a novel pharmacotherapeutic compound for the treatment of cocaine addiction.     

Conditioned place preference after single doses or "binge" cocaine in C57BL/6J and 129/J mice

The rewarding effect of cocaine as reflected by the development of conditioned place preference was examined in C57BL/6J and 129/J mice. Cocaine was administered in a single daily dose (2.5, 5, 10 and 20 mg/kg ip) or in a "binge" pattern (15 mg/kg ip x3, hourly). Mice remained in the conditioning compartment for 30 min immediately after each injection. Single injections of cocaine from 5 to 20 mg/kg induced conditioned place preference in each strain of mice. Only C57BL/6J mice developed conditioned place preference after "binge" cocaine administration. Both strains showed significantly greater locomotion in the conditioning compartment across the range of single doses of cocaine and after "binge" cocaine administration, but only 129/J mice showed sensitization. When mice that had received the single 10 mg/kg dose were retested 4 weeks later, the amount of time spent in the preferred side was significantly reduced compared to the initial test in the 129/J, but not in C57BL/6J mice. Thus, the persistence of conditioned place preference is strain dependent. The fact that 129/J mice did not develop conditioned place preference after "binge" cocaine administration, but did after single doses, suggests that the rewarding effects of cocaine are influenced by pattern of administration, a factor that may be relevant to the development of human cocaine addiction.     

Influence of the dose and the number of drug-context pairings on the magnitude and the long-lasting retention of cocaine-induced conditioned place preference in C57BL/6J mice

Rationale The place conditioning procedure is increasingly used to study relapse in drug seeking in mice. However, the retention course of drug-induced place preference has not been systematically characterized.Methods The effects of cocaine doses and number of conditioning trials on both the magnitude and the persistence of cocaine-induced conditioned place preference (CPP) were investigated in C57BL/6J mice. Twelve groups of animals were injected with saline, 4, 8 or 12 mg/kg cocaine (i.p.) and submitted to an unbiased counterbalanced place conditioning protocol including one, two or four drug-pairing sessions. Subsequently, the animals were tested at various time intervals after the last conditioning session.Results One cocaine-pairing session was insufficient to induce a CPP. Two and four pairing sessions resulted in significant place preferences of similar magnitude for all tested doses of cocaine, the place preference induced by the greatest number of pairing sessions being the strongest. In the two-pairing groups, place preference lasted less than 14 days for any tested dose of cocaine. In contrast, all four-pairing groups still showed significant place preference 28 days after the last conditioning session. However, the magnitude of cocaine place preference slowly declined at a rate that was dependent upon cocaine dose. On the 35-day post-conditioning interval, only the 12-mg/kg cocaine group still displayed a significant place preference, whereas place preference was undetectable at 42 and 56 days post-conditioning for all groups.Conclusions The number of cocaine-pairing sessions, but not cocaine dose, affected the magnitude of cocaine place preference in mice when tested 1 day after the last conditioning session. In contrast, both cocaine doses and the number of pairing sessions affected the persistence of cocaine place preference. Overall, these results demonstrate that cocaine-induced place preference is a long lasting phenomenon that is strongly affected by the number of drug-pairing trials.     

Caffeine place conditioning in rats: comparison with cocaine and ethanol

The present study employed the place conditioning technique to compare rewarding potential of caffeine with that of cocaine and ethanol. In Experiment 1 caffeine, cocaine and ethanol place conditioning were estimated independently, whereas in Experiments 2 and 3 the preference of the external cues associated with caffeine vs. cocaine and caffeine vs. ethanol was assessed in a single test. Caffeine (1.5 mg/kg, i.p.) cocaine (5 mg/kg, i.p.) and ethanol (1.2 g/kg, i.g.) did produce secondary reinforcing effects comparable in magnitude (Experiment 1). In Experiments 2 and 3 animals had the opportunity ‘to compare' rewarding effects of two drugs. Data showed that the preference of cocaine-paired cues was absolutely (100%) higher than those of caffeine, whereas reinforcing actions of caffeine and ethanol seemed to be equal. The proposed modification of conditioned place preference procedure may be useful for the comparison of rewarding values of different drugs with presumed addictive potential.     

Differential ability of D1 and D2 dopamine receptor agonists to induce and modulate expression and reinstatement of cocaine place preference in rats

Rationale D1-Like agonists are self-administered by drug-naive animals, whereas D2-like agonists reinstate cocaine-seeking behavior, but the rewarding and reinstating effects of D1- and D2-like agonists in pavlovian-based conditioned place preference are equivocal. Objective To compare the ability of D1 and D2 agonists to produce conditioned place preference with their modulation of expression and reinstatement of an established cocaine place preference. Methods Using an unbiased procedure, we measured the place preference induced by the D1 receptor agonist SKF 81297 and the D2/D3 receptor agonist quinpirole in drug-naive or cocaine-exposed rats. The rewarding effects of the D1 agonists SKF 82958, ABT-431, A-77636, and the D2/D3 receptor agonist 7-OH-DPAT were also tested. Additionally, we tested the ability of SKF 81297 and quinpirole to modulate expression and reinstatement of an established cocaine place preference. Results The D1 receptor agonists SKF 81297, SKF 82958, and ABT-431 produced dose-dependent conditioned place preferences, whereas A-77636 produced only place aversion, and the D2/D3 agonists quinpirole and 7-OH-DPAT were without effect in drug naive rats. In cocaine-treated rats, SKF-81297-induced place preference was reduced, whereas quinpirole-induced place preference was revealed. Pretreatment using either D1 or D2/D3 agonists blocked expression of an established cocaine place preference, but only the D1 agonist SKF 81297 and cocaine dose-dependently reinstated an extinguished cocaine place preference, whereas the D2/D3 agonist quinpirole induced place aversion but failed to alter cocaine-induced reinstatement. Conclusions D1, but not D2/D3, agonists mediate rewarding effects and reinstatement of cocaine place preference, but the reinstating effects differ markedly from self-administration paradigms.     

Reinstatement of nicotine-conditioned place preference by drug priming: effects of calcium channel antagonists

Reinstatement of drug-seeking behaviour in animals is relevant to drug relapse in humans. In the present study, we used the conditioned place preference paradigm to investigate the establishment, extinction, reinstatement and cross-reinstatement of nicotine-induced place conditioning in rats. Nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.5 mg/kg, i.p., three drug sessions). Once established, nicotine place preference was extinguished by repeated training. Following this extinction phase, the reinstatement of place conditioning was investigated. For this purpose, nicotine-experienced rats were challenged with nicotine (0.5 mg/kg, i.p.) or morphine (10 mg/kg, i.p.). These priming injections of both drugs renewed a marked preference for the compartment previously paired with nicotine. In the second step, we examined the influence of the calcium channel antagonists, nimodipine (10 and 20 mg/kg, i.p.) and flunarizine (5 and 10 mg/kg, i.p.), on the reinstatement of nicotine-conditioned place preference induced by priming doses of nicotine and morphine. It was shown that the calcium channel blockers dose dependently attenuated the reinstatement of nicotine place preference induced by both drugs. These findings support the hypothesis that similar neural calcium-dependent mechanisms are involved in nicotine- and morphine-induced reinstatement. Finally, the conditioned place preference paradigm appears to be a useful tool for studies of the relapse of drug-seeking behaviour in laboratory animals.     

Attenuation of cocaine-induced reinstatement of cocaine conditioned place preference by acamprosate

Acamprosate (calcium acetylhomotaurinate) is a glutamatergic neuromodulator efficacious at reducing relapse in alcoholic patients. The effect of acamprosate on relapse to other drugs of abuse has received little attention, however, and given increasing evidence that glutamatergic transmission mediates relapse to cocaine-seeking behavior, the purpose of this study was to assess the effects of acamprosate on the reinstatement of a conditioned place preference for cocaine. Mice were conditioned daily with cocaine (15 mg/kg), tested for the establishment of cocaine conditioned place preference, and then retested once weekly to monitor the extinction of the place preference. Following extinction of cocaine conditioned place preference, animals were treated daily with saline or acamprosate (30 or 100 mg/kg) for 3 days, followed by a single injection of cocaine (15 mg/kg) to reinstate conditioned place preference. In mice treated with saline or the low (30 mg/kg) dose of acamprosate, cocaine induced a significant reinstatement of the previously extinguished conditioned place preference; however, this reinstatement was not observed in mice treated with the high (100 mg/kg) dose of acamprosate. These results indicate that acamprosate can attenuate relapse-like behavior in mice and suggest that this compound may be potentially useful in the treatment for cocaine addiction.     

Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement

Rationale and objective

We sought to examine the impact of differing cocaine administration schedules and dosing on the magnitude of cocaine conditioned place preference (CPP), extinction, and stress- and cocaine-induced reinstatement of CPP.

Methods

First, in C57Bl/6J mice, we investigated whether total cocaine administration or pattern of drug exposure could influence the magnitude of cocaine CPP by conditioning mice with a fixed-low dose (F_L; 7.5 mg/kg; total of 30 mg/kg), a fixed-high dose (F_H; 16 mg/kg; total of 64 mg/kg), or an ascending dosing schedule (Asc; 2, 4, 8, and 16 mg/kg; total of 30 mg/kg). Next, we investigated if cocaine or saline is more effective at extinguishing preference by reconditioning mice with either a descending dosing schedule (Desc; 8, 4, 2, and 1 mg/kg) or saline. Finally, we examined if prior conditioning and reconditioning history alters stress (~2–3-min forced swim test) or cocaine-induced (3.5 mg/kg) reinstatement.

Results

We replicated and extended findings by Itzhak and Anderson (Addict. Biol. 17(4): 706–16, 2011) demonstrating that Asc conditioning produces a greater CPP than either the F_L or F_H conditioning schedules. The magnitude of extinction expressed was similar in the Desc reconditioned and saline groups. Moreover, only the saline, and not the Desc reconditioned mice, showed stress and cocaine-induced reinstatement of CPP.

Conclusions

Our results suggest that the schedule of cocaine administration during conditioning and reconditioning can have a significant influence on the magnitude of CPP and extinction of preference and the ability of cocaine or a stressor to reinstate CPP.     

Central administration of nociceptin/orphanin FQ blocks the acquisition of conditioned place preference to morphine and cocaine, but not conditioned place aversion to naloxone in mice

Rationale Previous studies have suggested that nociceptin (known also as orphanin FQ) suppresses the rewarding potential of morphine and alcohol in the rat. However, little is known of the effect of nociceptin on the rewarding properties of these and other drugs in the mouse.Objective To determine the effect of nociceptin on opiate or psychostimulant-induced conditioned place preference, or naloxone-induced conditioned place aversion in mice.Methods C57BL6 mice were implanted with chronically indwelling intracranial cannulae targeted at the lateral cerebroventricle through which nociceptin (0.06, 0.6, or 6 nmol) could be administered. Animals were conditioned in an unbiased balanced paradigm to study the effect of nociceptin administration alone, or the effect of nociceptin on the acquisition of place conditioning to morphine, cocaine, or naloxone (all 7.6 mg/kg subcutaneous).Results Administration of 0.06 nmol nociceptin alone stimulated locomotion during conditioning sessions, but had no hedonic effects. In contrast, administration of 6 nmol nociceptin alone markedly reduced basal locomotion during the conditioning sessions and induced a mild place aversion. Both morphine and cocaine induced robust place preferences, the acquisition of which was dose dependently suppressed by administration of nociceptin at doses of 0.6 nmol and above. Conditioning with naloxone produced a robust place aversion that was only weakly blocked by the maximum dose of nociceptin tested.Conclusion Nociceptin blocks the rewarding properties of drugs in both narcotic analgesic and psychostimulant classes in the mouse. In contrast, nociceptin has only a minor effect on the negative affective state experienced following naloxone administration.     

Postconditioning effects of magnesium on cocaine conditioned place preference in mice

Magnesium chloride (MgCl2) has recently been shown to have stimulant-like properties. Because stimulants are known to induce conditioned place preference (CPP), the CPP procedure was used to test the hypothesis that cocaine and MgCl2 share similar stimulus properties. This would be shown if cocaine-induced CPP could be enhanced in a postconditioning preference test by MgCl2 and other stimulants. Mice were conditioned with 5.0 mg/kg cocaine to the nonpreferred end of a three-compartment straight shuttle box. All groups showed significant shifts in preference from the preconditioning test to the postconditioning test. There were no changes in place preference over test days in mice that were injected only with saline and therefore not conditioned. When animals were given acute injections of either saline, 5.0 mg/kg cocaine, 1.0 mg/kg amphetamine, 30 mg/kg MgCl2, 10 mg/kg pentobarbital, or 0.25 mg/kg haloperidol following conditioning with cocaine, amphetamine and MgCl2 elevated the conditioned cocaine effect, and pentobarbital and haloperidol decreased the conditioned cocaine effect compared to saline. In addition, there was a dose-dependent influence of MgCl2, with 30 mg/kg producing the maximum effect on the conditioned cocaine effect.     

Rewarding and aversive properties of IP and SC cocaine: assessment by place and taste conditioning

Three experiments were conducted to compare the effectiveness of intraperitoneally (IP) administered or subcutaneously (SC) administered cocaine to produce place and/or taste conditioning after four conditioning trials. In each experiment, IP (5–20 mg/kg) cocaine produced a place preference, but SC (0.5–20 mg/kg) cocaine at concentrations that prevented necrosis, did not produce a place preference. The failure of SC cocaine to produce a place preference was not a function of conditioning trial duration. On the other hand, SC cocaine (20 mg/kg) produced conditioned taste avoidance, but IP cocaine (20 mg/kg) did not produce conditioned taste avoidance. The results suggest that IP cocaine, but not SC cocaine, is rewarding.     

Conditioned rewarding effects of morphine and methadone in mice pre-exposed to cocaine

BackgroundMethadone is widely accepted as the most effective treatment of opioid dependence. However, clinical observations indicate that the medication is less effective in individuals abusing cocaine. Diminished therapeutic efficacy of methadone in cocaine users is intriguing, but its mechanism has not been studied.MethodsHere, the conditioned place preference (CPP) procedure was used to examine the effects of the dose, number of conditioning sessions and pre-exposure to cocaine on the rewarding effects of morphine and methadone. Vehicle-pre-exposed and cocainesensitized mice (five injections of 10 mg/kg over 16 days) were conditioned using methadone (0, 0.1, 0.5, 3, and 5 mg/kg) or morphine (0, 1, and 10 mg/kg). Place preference was measured after one and again after two additional conditioning sessions.ResultsAs expected, morphine at 10 mg/kg produced CPP following just one conditioning session. While a single conditioning session with 1 mg/kg of morphine produced no CPP, the rewarding effect became apparent following two additional conditioning sessions as well as in mice pre-exposed to cocaine. Methadone produced CPP following one conditioning session at doses of 0.5, 3 and 5 mg/kg. However, unlike with morphine, methadone's rewarding effect was not enhanced by two additional conditioning sessions or by pre-exposure with cocaine.ConclusionsPrior exposure to cocaine increases unconditioned motivational effects of morphine but not of methadone.     

Enhanced ethanol-, but not cocaine-induced, conditioned place preference in Apoe(-/-) mice

Apolipoprotein (apo) E is a glycoprotein that is most commonly associated with cardiovascular and Alzheimer's disease risk. Recent data showing that apoE mRNA expression is reduced in the frontal cortex of alcoholics raise the possibility that apoE may also be related to the rewarding properties of ethanol. In this study, we examined whether Apoe deletion affects the rewarding properties of ethanol in mice. Male and female wild-type (WT; C57BL/6J) and apoE knockout (Apoe(-/-); C57BL/6J-Apoe(tm1Unc)) mice underwent an unbiased place conditioning procedure with ethanol (2 g/kg) or cocaine (5 mg/kg). Female mice were also tested for ethanol intake in a two-bottle choice procedure. Apoe(-/-) mice showed greater ethanol-induced conditioned place preference (CPP). In contrast, cocaine-induced CPP and ethanol intake were similar between the genotypes. These findings suggest that apoE normally reduces the conditioned rewarding properties of ethanol but not of cocaine. While the exact mechanisms underlying these effects of apoE are unknown, these data support a possible role for apoE in modulating the conditioned rewarding properties of ethanol.