Reinstatement Of Cocaine-induced Conditioned Place Preference Research Articles

Effects of Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 on the Reinstatement of Cocaine-Mediated Conditioned Place Preference in Mice.

A high percentage of relapse to compulsive cocaine-taking and cocaine-seeking behaviors following abstinence constitutes a major obstacle to the clinical treatment of cocaine addiction. Thus, there is a substantial need to develop effective pharmacotherapies for the prevention of cocaine relapse. The reinstatement paradigm is known as the most commonly used animal model to study relapse in abstinent human addicts. The primary aim of this study is to investigate the potential effects of systemic administration of glucagon-like peptide-1 receptor agonist (GLP-1RA) exendin-4 (Ex4) on the cocaine- and stress-triggered reinstatement of cocaine-induced conditioned place preference (CPP) in male C57BL/6J mice. The biased CPP paradigm was induced by alternating administration of saline and cocaine (20 mg/kg), followed by extinction training and then reinstatement by either a cocaine prime (10 mg/kg) or exposure to swimming on the reinstatement test day. To examine the effects of Ex4 on the reinstatement, Ex4 was systemically administered 1 h after the daily extinction session. Additionally, we also explored the associated molecular basis of the behavioral effects of Ex4. The expression of nuclear factor κβ (NF-κβ) in the nucleus accumbens (NAc) was detected using Western blotting. As a result, all animals that were treated with cocaine during the conditioning period successfully acquired CPP, and their CPP response was extinguished after 8 extinction sessions. Furthermore, the animals that were exposed to cocaine or swimming on the reinstatement day showed a significant reinstatement of CPP. Interestingly, systemic pretreatment with Ex4 was sufficient to attenuate cocaine- and stress-primed reinstatement of cocaine-induced CPP. Additionally, the expression of NF-κβ, which was upregulated by cocaine, was normalized by Ex4 in the cocaine-experienced mice. Altogether, our study reveals the novel effect of Ex4 on the reinstatement of cocaine-induced CPP and suggests that GLP-1R agonists appear to be highly promising drugs in the treatment of cocaine use disorder.

The Role of Beta-Endorphin in Cocaine-Induced Conditioned Place Preference, Its Extinction, and Reinstatement in Male and Female Mice.

Endogenous opioids have been implicated in cocaine reward. However, the role of each opioid peptide in this regard is unknown. Notably, the role of each peptide in extinction and reinstatement is not fully characterized. Thus, we assessed whether cocaine-induced conditioned place preference (CPP) and its extinction and reinstatement would be altered in the absence of beta-endorphin. We also examined if sex-related differences would exist in these processes. Male and female mice lacking beta-endorphin and their respective controls were tested for baseline place preference on day 1. On day 2, mice were treated with saline/cocaine (15 mg/kg) and confined to the vehicle- or drug-paired chamber for 30 min, respectively. In the afternoon, mice were treated with the alternate treatment and confined to the opposite chamber. Mice were then tested for CPP on day 3. Mice then received additional conditioning on this day as well as on day 4. Mice were then tested for CPP on day 5. Mice then received extinction training on day 9. On day 10, mice were tested for extinction and then reinstatement of CPP following a priming dose of cocaine (7.5 mg/kg). Male and female mice lacking beta-endorphin did not exhibit CPP following single conditioning with cocaine. On the other hand, only male mice lacking beta-endorphin failed to show CPP after repeated conditioning. Nonetheless, reinstatement of CPP was blunted in both male and female mice lacking beta-endorphin compared to controls. The present results suggest that beta-endorphin plays a functional role in cocaine-induced CPP and its reinstatement, and sex-related differences exist in the regulatory action of beta-endorphin on the acquisition but not reinstatement of cocaine CPP.

Hypericum perforatum L. prevents the acquisition of and promotes resilience against stress-induced reinstatement of the conditioned place preference induced by cocaine

Cocaine use disorder is a serious problem worldwide, and there are no approved medications for its treatment. A novel approach to the treatment of drug addiction is the use of natural products, and, in this context, preclinical evidence suggests that Hypericum perforatum L. (Hypericum) is effective against alcohol and other substance use disorders. We hypothesised that Hypericum could also be useful as a treatment for cocaine use disorder, and so we set out to test its effectiveness in a mice model of cocaine addiction. In the first experiment we evaluated its effects on the acquisition of cocaine-induced conditioned place preference (CPP). Adult male mice were conditioned with cocaine (25 mg/kg), cocaine with Hypericum (75, 150 or 300 mg/kg) or the plant extract alone (300 mg/kg). In the second experiment, we tested the effects of Hypericum on stress-induced reinstatement of cocaine CPP. All the mice were conditioned with cocaine (25 mg/kg) and, after extinction of CPP, the reinstating effects of social defeat (alone or with 75, 150 or 300 mg/kg of Hypericum) were evaluated. All the doses of Hypericum prevented the acquisition of cocaine-induced CPP. Furthermore, the plant extract dose-dependently reduced the reinstating effects of social defeat. Therefore, Hypericum is effective in reducing the rewarding effects of cocaine and prevents the stress-induced reinstatement of cocaine CPP in mice. The mechanisms underlying these positive effects of Hypericum perforatum L. need to be determined by future research. Our results endorse Hypericum as a natural treatment for cocaine dependence.

Distinct Regulation of Dopamine D3 Receptor in the Basolateral Amygdala and Dentate Gyrus during the Reinstatement of Cocaine CPP Induced by Drug Priming and Social Stress.

Relapse in the seeking and intake of cocaine is one of the main challenges when treating its addiction. Among the triggering factors for the recurrence of cocaine use are the re-exposure to the drug and stressful events. Cocaine relapse engages the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which are responsible for emotional and episodic memories. Moreover, D3 receptor (D3R) antagonists have recently arisen as a potential treatment for preventing drug relapse. Thus, we have assessed the impact of D3R blockade in the expression of some dopaminergic markers and the activity of the mTOR pathway, which is modulated by D3R, in the BLA and DG during the reinstatement of cocaine-induced conditioned place preference (CPP) evoked by drug priming and social stress. Reinstatement of cocaine CPP paralleled an increasing trend in D3R and dopamine transporter (DAT) levels in the BLA. Social stress, but not drug-induced reactivation of cocaine memories, was prevented by systemic administration of SB-277011-A (a selective D3R antagonist), which was able, however, to impede D3R and DAT up-regulation in the BLA during CPP reinstatement evoked by both stress and cocaine. Concomitant with cocaine CPP reactivation, a diminution in mTOR phosphorylation (activation) in the BLA and DG occurred, which was inhibited by D3R blockade in both nuclei before the social stress episode and only in the BLA when CPP reinstatement was provoked by a cocaine prime. Our data, while supporting a main role for D3R signalling in the BLA in the reactivation of cocaine memories evoked by social stress, indicate that different neural circuits and signalling mechanisms might mediate in the reinstatement of cocaine-seeking behaviours depending upon the triggering stimuli.

Transient receptor potential vanilloid 1 mediates cocaine reinstatement via the D1 dopamine receptor in the nucleus accumbens.

The transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that mediates synaptic modification in the nucleus accumbens (NAc). However, no study has yet examined the mechanism of TRPV1 in the NAc on cocaine reinstatement. We investigated the mechanism of TRPV1 in NAc on cocaine reinstatement using the conditioned place preference (CPP) test in mice. We examined the effect of capsazepine (5 mg/kg, a TRPV1 antagonist, administered intraperitoneally (i.p.)), capsaicin (0.3 mg/kg, a TRPV1 agonist, administered i.p.), and genetic deletion of TRPV1 on the reinstatement of cocaine-induced CPP (15 mg/kg, administered i.p.). The expression of TRPV1 and Ca2+/calmodulin-mediated kinase II (CaMKII) in the NAc were determined after cocaine reinstatement. Microinjection of SB366791 (0.2 ng, a selective TRPV1 antagonist) in the NAc was assessed on SKF-81297 (1 µg, D1-like dopamine (DA) receptor agonist) primed cocaine reinstatement. Capsazepine suppressed and capsaicin potentiated cocaine CPP in the reinstatement phase. In addition, genetic deletion of TRPV1 inhibited cocaine-priming reinstatement. Cocaine reinstatement was mediated by increased TRPV1 expression in the NAc, which involves CaMKII. Microinjection of SB366791 in the NAc prevented the cocaine reinstatement evoked by microinjection of SKF-81297 in the NAc. These findings suggest that activation of TRPV1 mediates the stimulation of D1-like DA receptors and CaMKII in the NAc, resulting in the facilitation of cocaine reinstatement behaviors. Thus, our findings reveal a previously unknown TRPV1 mechanism in the reinstatement to drugs of abuse.

Modulation of stress- and cocaine prime-induced reinstatement of conditioned place preference after memory extinction through dopamine D3 receptor

Accumulating evidence indicates that dopamine (DA) D3 receptor (DAD3R) antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the selective DAD3R antagonist SB-277011-A on the reinstatement of cocaine-induced conditioned place preference (CPP) produced by a priming dose of cocaine, by social defeat stress and by two kinds of physiological stressors (restraint and tail pinch) in male adult mice. We also explored reinstatement-related plasma corticosterone levels (as marker of stress response) and the effects of blocking DAD3R. Administration of SB-277011-A (24 or 48 mg/kg i.p.) did not modify conditioned reinstatement of cocaine seeking triggered by cocaine prime. By contrast, we found that the vulnerability to reinstatement of the CPP of defeated animals that have undergone CPP extinction was abolished by the DAD3R antagonist (24 mg/kg) given 30 min before the test session. Reactivation of the CPP response produced by physiological stress stimuli was also attenuated by SB-277011-A (48 mg/kg i.p.). On the other hand, the blockade of DAD3R significantly prevented the increased corticosterone release during reinstatement of cocaine-induced CPP that was seen in social defeated animals, in mice suffering physiological stress and after cocaine prime. Present results demonstrate a modulation by DAD3R of the reactivation of the incentive value of cocaine-associated cues induced by social and physiological stress stimuli, which was associated to a glucocorticoid-dependent mechanism. Our results also point to a possible potential therapeutic use of selective DAD3R antagonists for the prevention of stress-induced cocaine-seeking and relapse.

Nicotine pretreatment reduced cocaine-induced CPP and its reinstatement in a sex- and dose-related manner in adult C57BL/6J mice

Previous preclinical studies have shown that nicotine pretreatment during adolescence increases the reinforcing actions of cocaine. However, little is known about the effect of prior nicotine administration on cocaine-induced conditioned place preference (CPP) and its reinstatement in adult mice. Besides, little information is available regarding the role of sex in this cross-talk between nicotine and cocaine. Thus, we examined if nicotine administration during adulthood would differentially alter cocaine-induced CPP, its extinction and reinstatement in male versus female mice and if the dose of nicotine was important in this regard. To this end, mice were pretreated with saline or nicotine (0.25 or 1mg/kg; twice daily for seven days) and then tested for place preference before and after single and repeated conditioning with cocaine (15mg/kg). Mice were then exposed to extinction training and tested for reinstatement of CPP. Our results showed that male and female mice pretreated with saline and conditioned with cocaine each exhibited a robust CPP after a single cocaine conditioning. However, this response was blunted in mice pretreated with the lower but not higher dose of nicotine. Female mice pretreated with the lower dose nicotine also failed to show CPP after repeated conditioning. Reinstatement of cocaine-induced CPP was also blunted in these mice compared to their respective controls. Together, these results suggest that nicotine administration during adulthood exerts differential effects on cocaine-induced CPP and its reinstatement in male and female mice and the dose of nicotine is important in this regard.

The effect of phosphodiesterase inhibitors on the extinction of cocaine-induced conditioned place preference in mice

Several phosphodiesterase inhibitors (PDEis) improve cognition, suggesting that an increase in brain cAMP and cGMP facilitates learning and memory. Since extinction of drug-seeking behavior requires associative learning, consolidation and formation of new memory, the present study investigated the efficacy of three different PDEis in the extinction of cocaine-induced conditioned place preference (CPP) in B6129S mice. Mice were conditioned by escalating doses of cocaine which was resistant to extinction by free exploration. Immediately following each extinction session mice received (a) saline/vehicle, (b) rolipram (PDE4 inhibitor), (c) BAY-73-6691 (PDE9 inhibitor) or (d) papaverine (PDE10A inhibitor). Mice that received saline/vehicle during extinction training showed no reduction in CPP for >10 days. BAY-73-6691 (a) dose-dependently increased cGMP in hippocampus and amygdala, (b) significantly facilitated extinction and (c) diminished the reinstatement of cocaine CPP. Rolipram, which selectively increased brain cAMP levels, and papaverine which caused increases in both cAMP and cGMP levels, had no significant effect on the extinction of cocaine CPP. The results suggest that increase in hippocampal and amygdalar cGMP levels via blockade of PDE9 has a prominent role in the consolidation of extinction learning.

Effects of d-cycloserine on extinction and reinstatement of morphine-induced conditioned place preference

d-Cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine recognition site on the N-methyl- d-aspartate (NMDA) receptor complex, has been shown to facilitate the extinction and prevent the relapse of cocaine-induced conditioned place preference (CPP) when administered before or after each extinction trail. However, some studies have suggested that DCS does not influence or even enhance relapse of seeking behavior on cocaine self-administration (SA) in rats or cocaine-dependent individuals undergoing clinical exposure treatment. Furthermore, there are no reports on the effects of DCS and the extinction of morphine-conditioned behaviors in mice. The present study investigated the effects of DCS on extinction by exposing mice to drug-paired cues and the subsequent reinstatement of morphine-primed CPP. Our results showed that DCS at doses of 7.5, 15, and 30 mg/kg did not induce conditioned appetitive or aversive effects and DCS combined with morphine conditioning failed to affect the acquisition of morphine-induced CPP. Moreover, pretreatment with DCS (7.5, 15, and 30 mg/kg, i.p.) prior to extinction training had no significant effects on the extinction and subsequent morphine-primed reinstatement of morphine-induced CPP. These results suggested that DCS may not be a powerful adjunct for cue exposure therapy of opioid addiction. In view of differing outcomes in both preclinical and clinical studies, the potential of DCS in exposure treatment of drug-seeking behaviors should be carefully evaluated.

Social experiences affect reinstatement of cocaine-induced place preference in mice

Drug addiction is a multifactorial disorder resulting from an interaction between genetic and environmental factors, and negative and positive environmental conditions may increase or reduce, respectively, vulnerability to drug addiction. The influence of different social experiences on the acquisition, extinction, and reinstatement of a cocaine-induced conditioned place preference (CPP) was evaluated. In experiment 1, adolescent and adult male OF1 mice housed under four different conditions (grouped, isolated, crowded, and cohabitating with a female) were conditioned with 50, 12.5, or 3.125 mg/kg of cocaine. All mice underwent extinction sessions until the CPP was extinguished. The effects of cocaine priming injections on the reinstatement of CPP were then evaluated. In experiment 2, the effect of different social experiences on the maintenance and reinstatement of cocaine-CPP in adult mice was studied. Although housing conditions did not affect the acquisition of cocaine-CPP, it did modify reinstatement after extinction. Adolescent mice living in crowded conditions or cohabitating with a female did not present reinstatement after cocaine priming. Similarly, neither isolated adult mice nor adults cohabitating with a female presented reinstatement. In grouped adult mice, isolation after acquisition of the CPP and social defeat before reinstatement increased the vulnerability to reinstatement induced by cocaine priming. Conversely, both exposure to females and a brief social interaction undermined cocaine-induced reinstatement. Social experiences modify vulnerability to reinstatement, acting as prevention or risk factors in the development of drug addiction.

PRECLINICAL STUDY: The effect of naltrexone on amphetamine‐induced conditioned place preference and locomotor behaviour in the rat

Whereas amphetamine and other psychostimulants primarily act on the dopamine system, there is also evidence that other neurotransmitter systems, such as the endogenous opioid system, modulate psychostimulant-induced effects. Several studies have investigated the role of opioid antagonists on cocaine-induced conditioned place preference (CPP), but there is limited information about the interaction with amphetamines. The aim of the present study was to investigate the effect of the opioid receptor antagonist, naltrexone (NTX) on the conditioning, expression and reinstatement of amphetamine-induced place preference. In addition, the effect of NTX on locomotor behaviour was measured during all sessions. During training, animals were conditioned with amphetamine (2 mg/kg) to induce place preference. In order to extinguish the conditioned behaviour, animals received saline for 12 days. Reinstatement of CPP was induced by a priming dose of amphetamine (0.5 mg/kg). The interaction of NTX and amphetamine was evaluated using three paradigms of CPP: with NTX (vehicle, 0.3, 1.0 and 3.0 mg/kg) administered either 30 minutes prior to amphetamine conditioning, or 30 minutes before the expression, or 30 minutes before the amphetamine priming to induce reinstatement. Naltrexone had no effect on the conditioning, the expression or the reinstatement induced by a priming dose of amphetamine. Further, NTX by itself did not induce place preference or place aversion. In contrast, NTX significantly attenuated the locomotor response to a priming dose of amphetamine without affecting general locomotor behaviour. The results suggest differences in opioid modulation of amphetamine-induced behaviours in the rat.

Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats

Brain-derived neurotrophic factor (BDNF) is involved in the survival and function of midbrain DA neurons. BDNF action is mediated by the TrkB receptor-tyrosine kinase, and both BDNF and TrkB transcripts are widely expressed in the rat mesolimbic pathway, including the nucleus accumbens (NAc) and the ventral tegmentum area (VTA). BDNF was previously shown to be involved in cocaine reward and relapse, as assessed in rat models. The goal of this study is to explore the role of BDNF and TrkB in the rat nucleus accumbens (NAc) in cocaine-induced psychomotor sensitization and in conditioned-place preference acquisition, expression, and reinstatement. In vivo genetic manipulations of BDNF and TrkB were performed using a lentiviral gene delivery approach to over-express these genes in the NAc and siRNA-based technology to locally knockdown gene expression. Behavioral experiments consisted of locomotor activity monitoring or cocaine-induced conditioned-place preference (CPP). BDNF and/or its receptor TrkB in the NAc enhance drug-induced locomotor activity and induce sensitization in rats. Furthermore, LV-BDNF- and LV-TrkB-treated rats display enhanced cocaine-induced CPP, delayed CPP-extinction upon repeated measurements, and increased CPP reinstatement. In contrast, expression of TrkT1 (truncated form of TrkB, acting as a dominant negative) inhibits these behavioral changes. This inhibition is also observed when rats are fed doxycycline (to block lentivirus-mediated gene expression) or when injected with siRNAs-expressing lentiviruses against TrkB. In addition, we investigate the establishment, maintenance, extinction, and reinstatement of cocaine-induced CPP. We show that BDNF and TrkB-induced CPP takes place during the learning period (conditioning), whereas extinction leads to the loss of CPP. Extinction is delayed when rats are injected LV-BDNF or LV-TrkB, and in turn, priming injections of 2 mg/kg of cocaine reinstates it. These results demonstrate the crucial function of BDNF-through its receptor TrkB-in the enhancement of locomotor activity, sensitization, conditioned-place preference, CPP-reinstatement, and rewarding effects of cocaine in the mesolimbic dopaminergic pathway.

Effects of urokinase-type plasminogen activator in the acquisition, expression and reinstatement of cocaine-induced conditioned-place preference

Cocaine and many other psychostimulants strongly induce urokinase-type plasminogen activator (uPA) expression in the mesolimbic dopaminergic pathway, which plays a major role in drug-mediated behavioral plasticity [Bahi A, Boyer F, Gumy C, Kafri T, Dreyer JL. In vivo gene delivery of urokinase-type plasminogen activator with regulatable lentivirus induces behavioral changes in chronic cocaine administration. Eur J Neurosci 2004;20:3473–88; Bahi A, Boyer F, Kafri T, Dreyer JL. Silencing urokinase in the ventral tegmental area in vivo induces changes in cocaine-induced hyperlocomotion. J Neurochem 2006;98:1619–31; Bahi A, Dreyer JL. Overexpression of plasminogen activators in the nucleus accumbens enhances cocaine-, amphetamine- and morphine-induced reward and behavioral sensitization. Genes Brain Behav 2007]. In this study, the role of mesolimbic dopamine (DA) pathways in the development of cocaine reward was examined by conditioned-place preference in rats with bilateral intra-accumbens injections of uPA-expressing lentiviral vectors. We show that overexpression of uPA in the Nac significantly augments cocaine-induced place preference. Furthermore, while this did not affect the ability of preference to be extinguished, reinstatement with a low dose of cocaine produced significantly greater preference to the cocaine-associated context. Once CPP had been established, and the preference extinguished, reinstatement induced by a priming dose of cocaine was facilitated by uPA. Inhibition of this serine protease expression using doxycycline abolished the augmented acquisition produced by overexpression of uPA but not the expression of the cocaine-induced CPP. When uPA is inhibited during the acquisition phase, animals no longer demonstrate place preference for the environment previously paired with cocaine. B428, a specific uPA inhibitor does not affect drug reinstatement after extinction if uPA has been activated during acquisition, a clear indication that uPA is involved in the acquisition phase of conditioned-place preference. Our results suggest that that increased uPA expression with repeated drug exposure produces conditions for enhanced acquisition of cocaine-induced CPP, indicating that cocaine-induced CPP and reinstatement may be dependent on active extracellular uPA.

Contribution of the suprachiasmatic nucleus to day:night variation in cocaine-seeking behavior

Recent work has shown that time-of-day influences drug-seeking behavior. The present experiments tested the hypothesis that the master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus (SCN) is required for generating day:night differences in drug-seeking behavior, specifically the acquisition, extinction, and reinstatement of cocaine-induced conditioned place preference (CPP). Sham and SCN-lesioned (SCNx) rats were trained for cocaine-induced CPP behavior at either ZT4 ( Zeitgeber time 4, 4 h after lights-on) or ZT12 (lights-off). After being tested for side preference, rats were allowed to extinguish CPP. This was followed by cocaine-induced reinstatement with 5 mg/kg and 10 mg/kg of cocaine. SCNx animals exhibited no 24-h locomotor activity rhythm. Acquisition of CPP behavior did not vary with time-of-day, but was greater in SCNx animals. Sham rats tested at ZT12 took significantly longer to extinguish CPP behavior compared to ZT4, an effect completely abolished by SCN lesions. Cocaine-induced reinstatement of CPP did not vary with time of day in sham rats. However, SCNx animals tested at ZT4 trended towards greater reinstatement to the low dose of cocaine, and displayed significantly less reinstatement to the higher dose of cocaine than sham rats. Additionally, SCNx rats tested for reinstatement to the lower dose of cocaine displayed greater reinstatement at ZT4 than at ZT12. We conclude that: 1) acquisition of CPP behavior does not vary between the two times of day tested but is influenced tonically by the SCN, 2) extinction of cocaine CPP varies with time-of-day and this variation depends critically on the SCN, and 3) reinstatement of cocaine CPP does not vary between the two times of day tested. However, day:night differences in reinstatement are unmasked in animals lacking an SCN, suggesting the possibility that an extra-SCN oscillator is responsible for generating variation in this cocaine-seeking behavior.

Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine after extinction

To explore the way in which drugs act to reinstate drug-seeking behavior, we studied drug-induced reinstatement of a cocaine-induced conditioned place preference (CPP). In a series of experiments, we studied the establishment, maintenance, extinction and reinstatement of a cocaine-induced CPP in a three-chamber ‘unbiased’ apparatus. Groups of rats were given four 20-min pairings of one chamber with cocaine (10.0 mg/kg, i.p.) and four of the other with saline on alternate days. In 15-min tests for CPP, drug-free rats were placed in the center choice chamber with access to the entire apparatus. Experiments were designed to study the expression of the CPP, the maintenance of the CPP in tests given at 2, 4, and 6 weeks after training, and the reinstatement of the CPP by cocaine (5.0 mg/kg) after extinction by 12 repeated tests in the non-drugged state, and after extinction by pairing each chamber, on alternate days, with saline on four occasions. Robust CPPs were obtained that endured for 4 weeks and were maintained for up to 6 weeks when tests were given at 2-week intervals. Both extinction procedures led to the loss of the CPP that was in turn reinstated by priming injections of cocaine. These results indicate that a cocaine-induced CPP, once developed, endures for several weeks, and is maintained by occasional testing even in the absence of additional drug experience. The fact that the CPP is easily reinstated when testing is preceded by a priming injection of cocaine suggests that drugs may induce relapse by renewing the incentive value of drug-associated cues.