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.     

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.     

D-serine facilitates the effectiveness of extinction to reduce drug-primed reinstatement of cocaine-induced conditioned place preference

Addiction is a disease that is characterized by compulsive drug-seeking and use despite negative health and social consequences. One obstacle in treating addiction is a high susceptibility for relapse which persists despite prolonged periods of abstinence. Relapse can be triggered by drug predictive stimuli such as environmental context and drug associated cues, as well as the addictive drug itself. The conditioned place preference (CPP) behavioral model is a useful paradigm for studying the ability of these drug predictive stimuli to reinstate drug-seeking behavior. The present study investigated the dose-dependent effects of D-serine (10?mg/kg, 30?mg/kg and 100?mg/kg) on extinction training and drug-primed reinstatement in cocaine-conditioned rats. In the first experiment, D-serine had no effect on the acquisition or development of cocaine-induced locomotor sensitization or CPP. In the second experiment, D-serine treatment resulted in significantly decreased time spent in the drug-paired compartment following completion of an extinction protocol. A cocaine-primed reinstatement test indicated that the combination of extinction training along with D-serine treatment resulted in a significant reduction of drug-seeking behavior. The third experiment assessed D-serine's long-term effects to diminish drug-primed reinstatement. D-serine treatment given during extinction was effective in reducing drug-seeking for more than four weeks of abstinence after the last cocaine exposure. These findings demonstrate that D-serine may be an effective adjunct therapeutic agent along with cognitive behavioral therapy for the treatment of cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'.     

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.     

The effects of acquisition training schedule on extinction and reinstatement of cocaine self-administration in male rats

Partial reinforcement is known to increase resistance to extinction (Rn) relative to training with continuous reinforcement. This phenomenon, referred to as the partial reinforcement extinction effect, is one of the most robust in learning and conditioning studies. Experiment 1 investigated manipulations known to affect the partial reinforcement extinction effect and determined their possible relevance for drug use patterns. Male rats received intravenous cocaine self-administration training under partial reinforcement (FR-10) training or continuous reinforcement (FR-1) conditions with either a low (0.25 mg/kg infusion) or a high cocaine dose (1.00 mg/kg infusion). Animals were placed on an extinction (recurrent nonreward) schedule for 10 days (1-hr sessions) prior to being tested for cue-induced reinstatement (single 2-hr session). Experiment 2 involved acquisition of cocaine self-administration under FR-1 conditions of short training (15 days) or extended training (30 days) with a low dose (0.25 mg/kg infusion) or a medium dose (0.50 mg/kg infusion) of cocaine reward prior to extinction or reinstatement. Experiment 1 showed that rats trained with FR-10-high dose outcomes exhibited greater Rn than the remaining groups. Additionally, FR-10-high dose and FR-10-low dose rats were more likely to return to active drug seeking during the reinstatement test. In Experiment 2, rats trained under FR-1-medium dose conditions were more persistent during extinction following short acquisition training than comparable rats experiencing extended acquisition training. The reinstatement test was conducted following extinction, in which it was observed that overtraining under FR-1-medium dose reward schedules resulted in a decrease in the tendency to return to active drug seeking.     

Attenuated incubation of cocaine seeking in male rats trained to self-administer cocaine during periadolescence

Rationale and objectives  Although onset of drug use during adolescence appears to increase long-term vulnerability to drug dependence in humans, relatively little is known about extinction and reinstatement of drug seeking after periadolescent onset of drug self-administration in laboratory animals. Furthermore, although cue-induced reinstatement of cocaine seeking increases progressively during abstinence from cocaine self-administration in adult subjects, this “incubation of cocaine craving” remains unexplored after adolescent drug intake in animal models. Materials and methods  We allowed periadolescent (postnatal day (PND) 35 at start) and adult (PND 83–95 at start) male Wistar rats to self-administer cocaine (0.36 mg/kg/infusion) in 2-h daily sessions on a fixed ratio 1 schedule of reinforcement over 14 days. Then, we compared extinction and cue-induced or cocaine priming-induced reinstatement (10 mg/kg cocaine, intraperitoneal) of cocaine seeking in both age groups after 30 days of abstinence in home cages. In separate cohorts, we tested for time-dependent increases in cue-induced reinstatement over approximately 1, 14, 30, or 60 days of abstinence in both age groups. Results  Adolescent and adult rats self-administered similar amounts of cocaine. Subsequent cue-induced reinstatement was lower in the adolescent-onset group after a 30-day abstinence period, but cocaine priming-induced reinstatement did not differ across ages. Also, extinction responding and time-dependent increases in cue-induced reinstatement (incubation) were less pronounced in rats that took cocaine as adolescents compared with adults. Conclusions  Surprisingly, these results may reflect resistance among adolescent subjects to some enduring effects of drug self-administration, such as reward learning.     

Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior in rats

Rationale Sex differences have been reported in physiological and behavioral responses to cocaine, but it is unclear whether sex differences exist in conditioned-cued relapse to cocaine seeking after prolonged abstinence. Furthermore, the role of estrous cyclicity in conditioned-cued relapse has not been investigated.Objective We assessed the influence of sex and estrous cyclicity on conditioned-cued reinstatement of drug-seeking behavior in Sprague–Dawley rats.Methods Rats were trained to self-administer intravenous cocaine (unconditioned stimulus, US; 0.25, 0.4, 0.5, 0.6, or 1.0 mg/kg per infusion) paired with light+tone conditioned stimuli (CSs) and were subsequently tested for the ability of the CSs to reinstate extinguished cocaine seeking (i.e., nonreinforced lever responding).Results Females exhibited more responding on the cocaine-paired lever during self-administration and extinction than males. Subsequently, males exhibited equally robust conditioned-cued reinstatement of extinguished drug-seeking behavior independent of cocaine training dose. Males and females trained on 0.4–0.6 mg/kg cocaine reinstated to a similar extent. However, females trained on the lowest dose (0.25 mg/kg) exhibited less reinstatement than males, and the source of this effect was the absence of reinstatement in estrous females. In addition, independent of estrous state, females trained on the highest dose (1.0 mg/kg) exhibited less reinstatement than males.Conclusions While males and females are equally responsive to cocaine-paired CSs when the conditions for CS–US association are optimal, females appear to attribute less motivational significance to the CS when it presumably acquires weaker motivational salience because of (a) a low cocaine dose or (b) weaker CS–US contiguity due to the prolonged effects of a high cocaine dose.     

Relationships between individual sensitivity to CS- and cocaine-induced reinstatement in the rat

Rationale. Maintaining abstinence is highly challenging for cocaine ex-users. Exposure to drug conditioned stimuli (CS) and to low doses of cocaine can provoke craving in humans and reinstate self-administration (SA) behavior in animal models. Whether drug- and CS-induced reinstatement depend on the same biological substrates remains controversial. Objectives. We investigated the relationships between cocaine- and CS-induced SA reinstatement within the same individuals as a function of the duration of the withdrawal period after cessation of extended cocaine SA. Methods. Sprague-Dawley rats were trained for cocaine intravenous SA (0.8 mg/kg per infusion) during 74 sessions (2 h daily exposure to cocaine) and submitted to withdrawal. Five and 30 days after the end of SA, cocaine- and CS-induced reinstatement were tested. Results. Both after a short and a long withdrawal, CS- and cocaine-induced reinstatement were not related. Furthermore, cocaine-induced reinstatement measured after a short and a long withdrawal was positively related while CS-induced reinstatement was not. The sensitivity of an individual to cocaine-induced reinstatement is not related to its sensitivity to CS-induced reinstatement. Furthermore, vulnerability to cocaine-induced reinstatement is determined quickly after SA cessation and is a long lasting state, whilst vulnerability to CS-induced reinstatement develops quickly or slowly depending on the individual. Conclusions. These results support the view that cocaine and CS induce reinstatement through different mechanisms. They imply that reinstatement in drug abuse is a heterogeneous condition with some individuals being more sensitive to one factor than to the other. Research for effective anti-relapse therapies should take these elements into account.     

Effects of the kappa opioid receptor antagonist, norbinaltorphimine, on stress and drug-induced reinstatement of nicotine-conditioned place preference in mice

Rationale

Several studies implicate stress as a risk factor for the development and maintenance of drug addictive behaviors and drug relapse. Kappa opioid receptor (KOR) antagonists have been shown to attenuate behavioral responses to stress and stress-induced reinstatement of cocaine and ethanol seeking and preference.

Objectives

In the current study, we determined whether the selective KOR antagonist, norbinaltorphimine (nor-BNI), would block stress-induced reinstatement of nicotine preference.

Methods

Adult Institute of Cancer Research mice were conditioned with 0.5 mg/kg nicotine, injected subcutaneously (s.c.) for 3 days and tested in the nicotine-conditioned place preference (CPP) model. After 3 days extinction, nor-BNI (10 mg/kg, s.c.) was administered 16 h prior to a priming dose of nicotine (0.1 mg/kg, s.c.), and mice were tested in the CPP model for nicotine-induced reinstatement of CPP. A separate group of mice was subjected to a 2-day modified forced swim test (FST) paradigm to induce stress after 3 days extinction from CPP. Mice were given vehicle or nor-BNI (10 mg/kg, s.c.) 16 h prior to each FST session.

Results

Nor-BNI pretreatment significantly attenuated stress-induced reinstatement of nicotine-CPP, but had no effect on nicotine-primed reinstatement.

Conclusions

Blockade of KORs by selective antagonists attenuates stress-induced reinstatement of nicotine-CPP. Overall, the kappa opioid system may serve as a therapeutic target for suppressing multiple signaling processes which contribute to maintenance of smoking, smoking relapse, and drug abuse in general.     

Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months

Rationale and objectives We previously found time dependent increases, or incubation, of cocaine seeking induced by re-exposure to cocaine cues over withdrawal periods of up to 3 months. Here, we studied cocaine seeking induced by re-exposure to cocaine cues or cocaine itself over an extended withdrawal period of 6 months.Methods Rats were trained to self-administer intravenous cocaine for 6 h/day for 10 days. Cocaine seeking induced by re-exposure to cocaine cues or cocaine itself, as measured in extinction or drug-induced reinstatement tests, respectively, was then assessed 1 day, or 1, 3 or 6 months after withdrawal. Rats were first given six 1-h extinction sessions wherein lever presses resulted in contingent presentations of cues previously paired with cocaine infusions. Subsequently, reinstatement of drug seeking induced by cocaine injections (expt 1: 0, 5, and 15 mg/kg, IP; expt 2: 0, 2.5, and 5 mg/kg) was assessed during three 1-h sessions.Results Profound time dependent changes in responsiveness to cocaine cues in the extinction tests were observed, with low responding after 1 day, high responding after 1 and 3 months, and intermediate responding after 6 months of withdrawal. In contrast, no significant time dependent changes in cocaine-induced drug seeking were found; acute re-exposure to cocaine effectively reinstated responding at all withdrawal periods.Conclusions Results indicate that the withdrawal period is a critical modulator of drug seeking provoked by re-exposure to cocaine cues, but not cocaine itself. Results also indicate that while the incubation of responsiveness to cocaine cues is a long lasting phenomenon, it is not permanent.     

Influence of abstinence and intervals between extinction trials on the expression of cocaine-conditioned place preference in adolescent rats

Rationale

Disruption of acquired drug–cue associations can effectively decrease relapse. The benefits of extinction training as opposed to abstinence have been reported. Timing of extinction trials is an important variable. Finding an effective extinction regimen can optimize addiction therapies.

Objective

To determine the effects of different drug-free periods on cocaine-conditioned place preference (CPP) in rats that either did or did not receive non-reinforced exposure to drug-associated stimuli.

Materials and methods

Male adolescent rats were trained for cocaine-CPP (5, 10, or 15 mg/kg, i.p.) in a biased manner for 8 days and then tested following different intervals.

Results

Rats treated with 15 mg/kg cocaine displayed high and equal CPP on the first test, performed 1, 4, 7, or 14 days following conditioning. Expression of CPP during the test performed 1 day after conditioning was equal in the groups conditioned with 5, 10, or 15 mg/kg cocaine. When the interval before the first test was extended to 14 days, the group treated with 5 mg/kg did not show CPP. Rats treated with the three doses and tested repeatedly at 1, 7, and 14 days did not display CPP on the third test. CPP after treatment with 10 or 15 mg/kg cocaine was already extinguished in the second test but only for an interval of 1–14 days.

Conclusions

Maintenance of CPP was evident at least 2 weeks after forced abstinence. Extinguished CPP can be obtained after a single extinction trial, performed close to original training and followed by prolonged abstinence. However, with low doses of cocaine, abstinence alone may be sufficient to disrupt drug–cue associations.     

Baclofen prevents drug-induced reinstatement of extinguished nicotine-seeking behaviour and nicotine place preference in rodents

The γ-aminobutyric acid(GABA)-B receptor agonist baclofen is known to reduce drug intake in both animals and humans and to prevent reinstatement of cocaine-, opioid-, and alcohol-seeking in rats after a period of extinction, but its effect on nicotine reinstatement is unknown. This study investigated the effect of baclofen on nicotine-seeking reinstatement both using the extinction/reinstatement model of nicotine self-administration and conditioned place preference (CPP). Results showed that in rats previously trained to intravenously self-administer nicotine (30 µg/kg/inf) under a FR-1 schedule of reinforcement, acute nicotine (0.15 mg/kg) priming effectively reinstates nicotine-seeking behaviour following extinction. At doses used in this study (up to 2.5 mg/kg) baclofen alone did not affect locomotor activity and did not reinstate responding. However, baclofen dose-dependently attenuated drug-induced reinstatement of nicotine-seeking in rats. Moreover, baclofen (1.25 mg/kg) completely blocked nicotine-induced reinstatement of extinguished nicotine (0.3 mg/kg) CPP in mice. Altogether, our results showed that baclofen is able to antagonise reinstatement of nicotine-seeking and CPP triggered by nicotine primings, suggesting its potential clinical utility as an anti-relapse agent.     

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.     

Susceptibility to conditioned place preference induced by addictive drugs in mice of the C57BL/6 and DBA/2 inbred strains

Rationale In previous studies, we have demonstrated that mice of the inbred strain C57BL/6J (C57) are more susceptible to amphetamine-induced conditioned place preference (CPP) than DBA/2J (DBA) mice. Moreover, we also observed parallel strain differences for the locomotor-stimulant effects of the drug. However, other studies have reported either no difference or opposite strain differences for cocaine- and morphine-induced CPP as well as for the locomotor effects of these drugs, suggesting that amphetamine-related behavioral phenotypes might depend on a specific pharmacological action of the psychostimulant. Objectives This study was aimed at testing strain differences for cocaine- and morphine-related behavioral phenotypes in the same experimental protocol and conditions previously used for amphetamine. Methods C57 and DBA mice were tested for CPP induced by cocaine (0, 5, 10, and 20 mg/kg) and morphine (0, 5, 7.5, and 10 mg/kg). Locomotor activity data were simultaneously obtained by measuring distance moved during all different CPP phases and unconditioned locomotor activity, behavioral sensitization and conditioned hyperactivity were measured together with CPP. Results (a) Either cocaine or morphine promoted significant CPP at lower doses in C57 than in DBA mice; (b) only drug-trained C57 mice showed a significant CPP compared with the control group; and (c) only C57 mice showed dose-dependent effects of cocaine on CPP. Moreover, there was no relationship between drug-induced CPP and locomotion. Conclusions The results demonstrate that C57 and DBA mice differ in their sensitivity to cocaine- and morphine-induced CPP and suggest that the two strains differ in sensitivity to the positive incentive properties of drugs of abuse.     

A comparison of the effects of different operant training experiences and dietary restriction on the reinstatement of cocaine-seeking in rats

Studies on the reinstatement of drug-seeking after withdrawal from chronic drug self-administration have varied in terms of the procedures by which animals are initially trained to self-administer the drug. The current study directly compared whether prior operant training for food pellet reinforcement and/or maintained dietary restriction significantly altered the reinstatement of extinguished cocaine-seeking in the presence of cocaine-paired cues, a priming injection of cocaine (10 mg/kg; i.p.), and the pharmacological stressor, yohimbine (1.25 or 2.5 mg/kg, i.p.). Male Long Evans rats were divided into four groups as follows: a) trained to lever press for food pellets prior to cocaine self-administration and then maintained on a restricted diet, b) trained to lever press for food pellets prior to cocaine self-administration and then placed on an ad libitum diet, c) untrained and maintained on a restricted diet, or d) untrained and placed on ad libitum feeding. All rats readily self-administered cocaine (0.2 mg/50 mul/infusion) and were subsequently extinguished in the absence of cocaine or previously cocaine-paired cues (light+tone). Following extinction, rats experienced cue-, cocaine-, and yohimbine-induced reinstatement testing. No significant differences were seen between groups for lever responding during the maintenance phase and during extinction. Likewise, reinstatement of cocaine-seeking did not vary across groups for cue-, cocaine-, or yohimbine-induced reinstatement. Under these specific parameters, operant training prior to cocaine self-administration and/or dietary restriction do not significantly alter reinstatement of cocaine-seeking. The results arguably support the approach of not using prior lever training with a non-drug reinforcer and to limit the use of dietary restriction only to the acquisition phase of drug self-administration.     

MDMA reinstates cocaine-seeking behaviour in mice

Background:MDMA effects are mediated by monoaminergic systems, which seem to play a central role in cocaine craving and relapse.Methods:CD1 mice trained to self-administer cocaine (1 mg/kg/infusion) underwent an extinction procedure in which the cues contingent with drug self-administration remained present. Mice achieving extinction were injected with MDMA (10 mg/kg), d-amphetamine (1 and 2 mg/kg) or saline and tested for reinstatement.Results:Acute MDMA, but not d-amphetamine or saline reinstated cocaine-seeking behaviour in mice in which cocaine self-administration and contingent cues were previously extinguished.Conclusions:Acute MDMA can reinstate cocaine-seeking behaviour in mice.     

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.     

Role of withdrawal in reinstatement of morphine-conditioned place preference

Rationale Relapse is a major characteristic of drug addiction and the primary problem in treating drug abuse. Based on the negative reinforcement view of addiction, in which the motivation to take drugs is thought to result from the desire to avoid the aversive effect of drug withdrawal, it has been theorized that withdrawal symptoms play a major role in the maintenance of and relapse to drug taking. However, the role of withdrawal in relapse has not yet been systemically investigated in the reinstatement model. Objectives Using a conditioned place preference (CPP) paradigm, we examined the role of different morphine withdrawal states (spontaneous withdrawal, naloxone-precipitated withdrawal, and conditioned withdrawal) in relapse to drug seeking. Methods Rats alternately received morphine (10 mg/kg, s.c.) and saline for 8 days to acquire the CPP. The morphine CPP disappeared after a 2-week extinction phase of saline-paired training. Rats were then chronically administered morphine to induce physical dependence. The different withdrawal states were induced and their roles in the reinstatement of extinguished CPP were assessed. During conditioned withdrawal, trunk blood samples were taken and the corticosterone level was measured by radioimmunoassay. To examine the role of corticotropin-releasing factor (CRF) receptor antagonist on conditioned-withdrawal-induced reinstatement of CPP, different doses of α-helical CRF (0.1 and 1 μg, i.c.v.) were administered 30 min prior to the CPP testing. Results The results show that morphine spontaneous withdrawal and naloxone-precipitated morphine withdrawal were ineffective in reinstating morphine CPP. However, the withdrawal cues significantly elicited the reinstatement of CPP and increased corticosterone level. Moreover, pretreatment with the CRF receptor antagonist α-helical CRF (1 μg, i.c.v.) significantly attenuated the effects of withdrawal cues on reinstatement of CPP and corticosterone levels. Conclusion These findings demonstrate that the cues associated with previous drug withdrawal play a major role in drug relapse and that activation of the CRF receptor is involved in conditioned-withdrawal-induced reinstatement. The present study suggests that CRF receptor antagonists might be of value in the treatment and prevention of relapse to drug seeking after long-term abstinence. Xin Ge and Wen Yue contributed equally to this work.     

Effects of withdrawal from chronic escalating-dose binge cocaine on conditioned place preference to cocaine and striatal preproenkephalin mRNA in C57BL/6J mice

Relapse is a serious problem for the effective treatment of cocaine addiction.RationaleExamining cocaine re-exposure-induced behavioral and neurobiological alterations following chronic escalating-dose binge cocaine administration and withdrawal may provide insight into the neurobiological basis of cocaine relapse.ObjectivesOur goal was to determine how exposure to chronic escalating-dose cocaine affects development of subsequent cocaine-induced conditioned place preference (CPP) and changes in endogenous opioid systems.MethodsMice were injected with either escalating-dose binge cocaine (15–30 mg/kg/injection × 3/day) or saline for 14-days and conditioned with 15 mg/kg of cocaine or saline (once per day for 10-days), starting either 1 or 14-days after the last day of binge injections.ResultsMice exposed to chronic escalating cocaine did not develop CPP to cocaine when conditioning commenced on the first day of withdrawal (CPP test on day 10 of withdrawal). By contrast, mice did develop CPP to cocaine when conditioning started on the 14th day of withdrawal (CPP test on day 24 of withdrawal). Furthermore, preproenkephalin (Penk) mRNA levels in caudate putamen were significantly higher in mice that received 14-day withdrawal from escalating-dose binge cocaine before the CPP procedure (tested 24 days post-binge) than those that received 1-day withdrawal (tested 10 days post-binge).ConclusionsThe rewarding effect of cocaine was blunted in early withdrawal from chronic escalating exposure, but recovered in more prolonged withdrawal. Time-dependent elevations in Penk mRNA levels may be part of the underlying mechanisms of this effect.     

Predictive validity of the extinction/reinstatement model of drug craving

 The effects of chronic desmethylimipramine (DMI) treatment on measures of incentive motivation for cocaine were assessed in order to investigate the predictive validity of the extinction/reinstatement model of drug craving. Rats were trained to respond for cocaine infusions (0.75 mg/kg per 0.1 ml IV) or received yoked-saline infusions during daily 3-h sessions. A light and tone were presented with the infusions. Following self-administration training, each group received daily injections of either saline or DMI (10 mg/kg, IP) for 21 days of withdrawal from the self-administration regimen. On days 12–21 of withdrawal, rats were allowed to respond in the absence of cocaine reinforcement (extinction phase). After reaching an extinction criterion of no responses for 1 h, the cocaine-paired stimuli were repeatedly presented to reinstate responding (reinstatement phase). In the control group, DMI treatment did not alter responding during either test phase, but increased the response latency during the extinction phase. In contrast, DMI treatment in the cocaine group decreased responding and increased the response latency during both test phases, and decreased the extinction latency during the extinction phase. Overall, the effects of DMI were consistent with a reduction of incentive motivation for cocaine, lending support for the predictive validity of the extinction/reinstatement model of drug craving. Received: 1 April 1997/Final version: 3 July 1997