Rewarding effects and reinstatement of MDMA-induced CPP in adolescent mice.

Although the rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in self-administration and conditioned place preference (CPP) procedures, its addictive potential (ie, the vulnerability to relapse, measured by its ability to induce reinstatement of an extinguished response), remains poorly understood. In this study, the effects of MDMA (5, 10, and 20 mg/kg) on the acquisition, extinction and reinstatement of CPP were evaluated in mice, using two different protocols during acquisition of CPP. In the first experiment, animals were trained using a two-session/day schedule (MDMA and saline for 4 consecutive days), whereas in the second experiment, they were trained using an alternating day schedule (MDMA and saline each 48 h). After extinction, the ability of drug priming to reinstate CPP was evaluated. In Experiment 1, MDMA did not significantly increase the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, although the preference was evident a week afterwards, lasting between 2 and 21 weeks. No reinstatement was observed after MDMA priming. In Experiment 2, all doses produced CPP in Post-C, which lasted between 1 and 4 weeks. MDMA induces reinstatement at doses up to 4 times lower than those used in conditioning. The analyses of brain monoamines revealed that the daily schedule of treatment induces a non-dose-dependent decrease in dopamine and serotonin (5-HT) in the striatum, whereas the alternating schedule produces a dose-dependent decrease of 5-HT in the cortex. These results demonstrate that MDMA produces long-lasting rewarding effects and reinstatement after extinction, suggesting the susceptibility of this drug to induce 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.     

Genetic liability increases propensity to prime-induced reinstatement of conditioned place preference in mice exposed to low cocaine

Rationale Relapse to drug use after periods of forced or self-imposed abstinence is a central problem in the treatment of addiction; therefore, identification of factors modulating the risk to relapse is a relevant goal of preclinical research. Objectives These experiments evaluated the influence of the amount of drug experienced, the duration of drug withdrawal, and individual liability on the propensity to cocaine-induced reinstatement of conditioned place preference (CPP). Materials and methods Mice from the inbred strains C57BL/6J and DBA/2J were trained for CPP with a high (20 mg/kg) or low (5 mg/kg) effective dose of cocaine. After CPP testing, all groups underwent extinction. Twenty-four hours after the extinction test, mice were challenged with saline, a cocaine dose unable to induce CPP (2.5 mg/kg) or an intermediate effective dose (10 mg/kg), and tested for CPP reinstatement. Additional groups of mice trained with the low cocaine dose were left undisturbed for 8 days after extinction test (long withdrawal), retested for extinction, and evaluated for prime-induced reinstatement (0, 2.5, 10 mg/kg of cocaine). Results Mice trained with the high cocaine dose, but not with the low one, showed prime-induced reinstatement 24 h after the extinction test; DBA/2J mice trained with the low dose showed reinstatement after long withdrawal. Conclusions These results indicate that reinstatement of CPP by cocaine prime depends on the amount of drug experienced and on an interaction between individual liability and duration of drug abstinence and suggest that the risk to relapse into drug seeking is not prevented by moderated drug consumption.     

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.     

Food restriction increases acquisition, persistence and drug prime-induced expression of a cocaine-conditioned place preference in rats

Cocaine conditioned place preference (CPP) is more persistent in food-restricted than ad libitum fed rats. This study assessed whether food restriction acts during conditioning and/or expression to increase persistence. In Experiment 1, rats were food-restricted during conditioning with a 7.0 mg/kg (i.p.) dose of cocaine. After the first CPP test, half of the rats were switched to ad libitum feeding for three weeks, half remained on food restriction, and this was followed by CPP testing. Rats tested under the ad libitum feeding condition displayed extinction by the fifth test. Their CPP did not reinstate in response to overnight food deprivation or a cocaine prime. Rats maintained on food restriction displayed a persistent CPP. In Experiment 2, rats were ad libitum fed during conditioning with the 7.0 mg/kg dose. In the first test only a trend toward CPP was displayed. Rats maintained under the ad libitum feeding condition did not display a CPP during subsequent testing and did not respond to a cocaine prime. Rats tested under food-restriction also did not display a CPP, but expressed a CPP following a cocaine prime. In Experiment 3, rats were ad libitum fed during conditioning with a 12.0 mg/kg dose. After the first test, half of the rats were switched to food restriction for three weeks. Rats that were maintained under the ad libitum condition displayed extinction by the fourth test. Their CPP was not reinstated by a cocaine prime. Rats tested under food-restriction displayed a persistent CPP. These results indicate that food restriction lowers the threshold dose for cocaine CPP and interacts with a previously acquired CPP to increase its persistence. In so far as CPP models Pavlovian conditioning that contributes to addiction, these results suggest the importance of diet and the physiology of energy balance as modulatory factors.     

Effects of varenicline and mecamylamine on the acquisition, expression, and reinstatement of nicotine-conditioned place preference by drug priming in rats

Nicotine addiction is a chronic disorder characterized by a relatively high rate of relapse even after long period of abstinence. In the present study, we used the conditioned place preference (CPP) paradigm to investigate the establishment, extinction, reinstatement, and cross-reinstatement of nicotine-induced place conditioning in rats. First, we revealed that nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.175 mg/kg, base, intraperitoneally (i.p.)). Once established, nicotine CPP was extinguished by repeated testing. Following this extinction phase, nicotine-experienced rats were challenged with nicotine (0.175 mg/kg, i.p.) or morphine (10 mg/kg, i.p.). These priming injections of both drugs induced a marked preference for the compartment previously paired with nicotine. Furthermore, given the important role of alpha4beta2 (a4b2) nicotinic receptor subtype in the acquisition and maintenance of nicotine dependence, we evaluated and compared the efficacy of varenicline, a partial a4b2 nicotinic receptor agonist (0.5, 1, and 2 mg/kg, subcutaneously (s.c.)), and mecamylamine (0.5, 1, and 2 mg/kg, s.c.), a non-selective nicotinic receptor antagonist, in blocking nicotine-induced CPP as well as reinstatement of nicotine CPP provoked by nicotine and morphine. It was shown that both nicotinic receptor ligands attenuated the acquisition and expression of nicotine CPP as well as the expression of reinstatement of nicotine CPP provoked by both drugs. Our results indicate similar cholinergic mechanisms, probably through the a4b2 receptors involved in the rewarding effects of nicotine and morphine in rats and may suggest that nicotinic receptors could be a potential target for developing pharmacotherapeutic strategies to treat and prevent nicotine and/or opioid addiction and relapse.     

100Hz电针对大鼠可卡因CPP重建的影响

目的:探讨100Hz电针对大鼠可卡因条件位置偏爱(Conditioned Place Preference,CPP)重建的影响.方法:采用可卡因诱导大鼠CPP重建模型,观察100 Hz电针对大鼠可卡因CPP重建的作用及选择性κ阿片受体拮抗剂nor-BNI对电针作用的影响.结果:100 Hz电针5次刺激抑制了可卡因(5 mg/kg)引燃CPP重建,nor-BNI(10μg/5μl)翻转了电针对可卡因CPP重建的抑制作用.结论:多次电针可通过κ阿片受体抑制可卡因引燃CPP的重建.     

Cocaine-induced conditioned place preference in mice: induction, extinction and reinstatement by related psychostimulants.

Reinstatement of drug-seeking behavior in animals is relevant to drug relapse in humans. In the present study, we employed the conditioned place preference (CPP) paradigm to investigate the extinction and reinstatement of the place-conditioned response, a model that is consistent with drug-seeking behavior. Cocaine-induced CPP was rendered in Swiss Webster mice and then extinguished after repeated saline injections (8 days) in both the previously cocaine-paired compartment and the saline-paired compartment. Following the extinction phase, the reinstatement of CPP was investigated. Cocaine-experienced mice were challenged with one of the following psychostimulants, cocaine (15 mg/kg), methamphetamine (METH; 0.5 mg/kg), methylphenidate (MPD; 20 mg/kg) and phencyclidine (PCP; 5 mg/kg). The priming injection of cocaine, METH and MPD, unlike PCP, induced a marked preference for the previously cocaine-paired compartment. This finding suggests that all three psychostimulants reinstated the CPP response, and METH and MPD substituted for the reinforcing cue of cocaine. A challenge injection of cocaine administered two and four weeks after the reinstatement of CPP indicated that CPP was maintained up to two weeks. The finding that METH and MPD but not PCP reinstated and supported cocaine-induced CPP suggests that the CPP paradigm may be a useful tool for drug discrimination studies and the reinstatement of drug-seeking behavior.     

Post-Retrieval Extinction Attenuates Cocaine Memories

Recent studies have shown that post-retrieval extinction training attenuates fear and reward-related memories in both humans and rodents. This noninvasive, behavioral approach has the potential to be used in clinical settings to treat maladaptive memories that underlie several psychiatric disorders, including drug addiction. However, few studies to date have used a post-retrieval extinction approach to attenuate addiction-related memories. In the current study, we attempted to disrupt cocaine-related memories by using the post-retrieval extinction paradigm in male Sprague Dawley rats. Results revealed that starting extinction training 1 h after cocaine contextual memory was retrieved significantly attenuated cocaine-primed reinstatement of conditioned place preference (CPP) and relapse of cocaine CPP (drug-free and cocaine-primed) following 30 days of abstinence. However, animals that did not retrieve the contextual cocaine memory before extinction training, or animals that began extinction training 24 h after retrieval (outside of the reconsolidation window), demonstrated normal cocaine CPP. Conversely, animals that received additional CPP conditioning, rather than extinction training, 1 h after reactivation of cocaine memory showed enhanced cocaine CPP compared with animals that did not reactivate the cocaine memory before conditioning. These results reveal that a behavioral manipulation that takes advantage of reconsolidation and extinction of drug memories may be useful in decreasing preference for, and abuse of, cocaine.     

Gamma-hydroxybutyric acid affects the acquisition and reinstatement of cocaine-induced conditioned place preference in mice

Cocaine addicts very often use different combinations of cocaine and other drugs of abuse such as gamma-hydroxybutyric acid. The objective of the present work was to evaluate the impact of gamma-hydroxybutyric acid administration on the rewarding actions of cocaine, using the conditioned place preference procedure. Cocaine-induced conditioned place preference (50 mg/kg) was studied after pairing this drug with different gamma-hydroxybutyric acid doses (6.25, 12.5, 25, 50 and 100 mg/kg) during either the acquisition or the expression phase of the procedure. After conditioned place preference had been established, and the preference was extinguished, a reinstatement was induced by a dose of cocaine half of that used to produce conditioning, or by gamma-hydroxybutyric acid alone or by both drugs together. The doses of 12.5 and 100 mg/kg of gamma-hydroxybutyric acid blocked the acquisition of cocaine-induced conditioned place preference, and no dose affected the expression of this conditioning. Reinstatement was abolished only with the dose of 25 mg/kg gamma-hydroxybutyric acid, which did not reinstate the preference by itself. This is the first study evaluating the effects of gamma-hydroxybutyric acid on the rewarding properties of cocaine using the conditioned place preference procedure. The principal conclusion of the study is that gamma-hydroxybutyric acid does not enhance the rewarding effect of cocaine, and within a narrow margin of effective doses, blocks the acquisition and reinstatement of cocaine-induced preference.     

Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness

Rationale

Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.

Objectives

The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs.

Methods

Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA).

Results

Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine.

Conclusions

These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence.

Highlights

? Topiramate increases the rewarding properties of cocaine in CPP? Topiramate alters dopaminergic signaling in the mesolimbic circuit? Topiramate delays the extinction of cocaine-induced CPP? TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine? Results show that it should limit the use of topiramate in cocaine-dependent subjects

     

Acute blockade of CB1 receptor leads to reinstatement of MDMA-induced conditioned place preference

Cannabis is one of the drugs most commonly consumed in combination with ecstasy (3,4-methylenedioxymethamphetamine, MDMA). Although numerous studies have attempted to further our understanding of the role of the cannabinoid system in drug abuse, few have focused on how it influences the rewarding effects of MDMA. The aim of the present study was to evaluate the role of the CB1 cannabinoid receptor in vulnerability to reinstatement of a MDMA-induced conditioned place preference (CPP). Mice were first conditioned with 5 mg/kg of MDMA. Once the preference had been extinguished, a priming dose of MDMA, alone or plus the CB1 cannabinoid agonist WIN 55,212-2 (0.1 and 0.5 mg/kg) or the CB1 cannabinoid antagonist SR 141716A (0.3 mg/kg), was administered on alternate days. The CB1 receptor antagonist, alone or with any of the priming doses of MDMA, induced reinstatement of the preference. In contrast, WIN 55,212-2 had no effect on reinstatement of the MDMA-induced CPP when administered alone, but potentiated the effects of subthreshold priming doses of MDMA. These results highlight the important role of the CB1 receptor in vulnerability to reinstatement of drug-seeking behavior and point to the importance of the endocannabinoid system in the addictive potential of MDMA.     

The facilitative effects of d-cycloserine on extinction of a cocaine-induced conditioned place preference can be long lasting and resistant to reinstatement

Rationale and objective

The N-methyl-d-aspartate receptor agonist, d-cycloserine (DCS), accelerates extinction of a cocaine-induced conditioned place preference (CPP) when given after daily extinction tests. Here, we studied the effects of DCS in rats given spaced-extinction sessions at 3- or 7-day intervals using two different extinction procedures.

Materials and methods

Rats were trained on a CPP (four cocaine, 10 mg/kg, i.p., and four saline pairings with one of two compartments). Immediately following the CPP test and all extinction tests (days 4, 7, 10, and 24, experiment 1), DCS (15 mg/kg, i.p.) or saline was administered. In experiment 2, extinction was conducted by exposing rats to the drug-paired cues for 2 or 20 min, three times, at 7-day intervals followed immediately by DCS or saline. After extinction, tests for retention and cocaine-induced reinstatement were given.

Results

In experiment 1, rats given DCS lost the cocaine CPP after one extinction trial, an effect that persisted for 2 weeks after the last DCS injection and that was resistant to cocaine-induced reinstatement. In experiment 2, extinction was facilitated by DCS compared to saline when rats received 2-min exposures to the conditioned stimulus. Longer 20-min exposures minus/plus repeated testing led to retention of extinction in both groups regardless of DCS treatment.

Conclusions

Extinction of appetitive conditioning is facilitated by DCS after 1–3 post-spaced trial injections, and retention is lasting and resistant to reinstatement. The facilitative effects appear early in extinction, but when extinction procedures are intensive, DCS appears to have no additional benefit.     

The anti-relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine

The effects of the anti-relapse compound acamprosate (calcium acetylhomotaurinate) on the conditioned rewarding effects of ethanol, cocaine and morphine were studied using the conditioned place preference (CPP) paradigm. During 3 days of drug conditioning, mice were pretreated with saline or acamprosate (30, 100 or 300 mg kg(-1) i.p.) 10 min prior to the administration of ethanol (2 g kg(-1) i.p.), cocaine (15 mg kg(-1) i.p.) or morphine (10 mg kg(-1) i.p.), and subsequently confined to one of two distinct conditioning chambers. On the following day, mice were tested for the expression of CPP. Acamprosate dose-dependently reduced the development of CPP to ethanol and cocaine but not morphine. When tested as the conditioning drug, acamprosate alone produced neither a conditioned place preference nor aversion. These data suggest that acamprosate can suppress the conditioned rewarding effects of ethanol and certain classes of abused substances.     

Modulatory effects of low-dose MDMA on cocaine-induced locomotor activity and place conditioning in rats

Methylenedioxymethamphetamine (MDMA; “Ecstasy”) is commonly abused by humans in environments such as nightclubs and rave parties where other drugs of abuse are readily available. Despite the popularity of polysubstance abuse among recreational MDMA users, relatively few controlled experimental studies have documented the neurobehavioral effects of MDMA in combination with other abused substances. This study employed conditioned place preference procedures (CPP) to assess the locomotor activating and place conditioning effects of acute concurrent administration of MDMA (1.5 or 3.0 mg/kg) and cocaine (10 or 20 mg/kg) in rats. Results indicate that low dose MDMA can enhance the locomotor and conditioned rewarding effects of cocaine. These findings may have important implications for understanding the contribution of serotonergic-dopaminergic interactions in the abuse liability of MDMA when used in combination with cocaine or other psychostimulant drugs.     

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

INTRODUCTION: Prior activation of the kappa opioid system by repeated stress or agonist administration has been previously shown to potentiate the rewarding properties of subsequently administered cocaine. In the present study, intermittent and uncontrollable footshock, a single session of forced swim, or acute administration of the kappa agonist U50,488 (5 mg/kg) were found to reinstate place preference in mice previously conditioned with cocaine (15 mg/kg) and subsequently extinguished by repeated training sessions without drug. RESULTS AND DISCUSSION: Stress-induced reinstatement did not occur for mice pretreated with the kappa opioid receptor antagonist norbinaltorphimine (10 mg/kg) and did not occur in mice lacking either kappa opioid receptors (KOR -/-) or prodynorphin (Dyn -/-). In contrast, the initial cocaine conditioning and extinction rates were not significantly affected by disruption of the kappa opioid system. Cocaine-injection also reinstated conditioned place preference in extinguished mice; however, cocaine-primed reinstatement was not blocked by kappa opioid system disruption. CONCLUSION: The results suggest that stress-induced drug craving in mice may require activation of the dynorphin/kappa opioid system.     

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.     

Cocaine, but not alcohol, reinstates cocaine-induced place preferences

Alcohol has been reported to modulate the reinforcing and aversive properties of cocaine. Given these effects, the present study examined whether this interaction could be extended to cocaine seeking using the conditioned place preference (CPP) procedure. Specifically, 31 drug-naive, male Sprague-Dawley rats were injected every other day (for 8 days) with either 20 mg/kg cocaine or vehicle in an alternating sequence prior to being restricted to a drug or vehicle side of a place preference chamber for 30 min. On Day 9, subjects were given 15-min access to the entire chamber to assess compartment preference. Animals then underwent extinction by pairing both compartments with vehicle for an additional 8 days. Extinction was assessed in the same manner as place conditioning. The animals were then given priming injections of vehicle, 15 mg/kg cocaine, 0.5 or 1.0 g/kg alcohol on the day following the extinction test. Pairing 20 mg/kg cocaine with a specific compartment resulted in a significant place preference. Breaking the relation between the compartment and the drug by pairing both compartments with vehicle extinguished this preference. Interestingly, only 15 mg/kg cocaine was able to reinstate the cocaine-induced place preference, suggesting that the ability to reinstate cocaine seeking may be drug specific.