Conditioned hyperkinesia induced by cocaine in mice is dose-dependent but not correlated with the unconditioned response or the contextually-sensitized response

The aims of the study were to test whether drug dose is positively related to the magnitude of the conditioned response following sensitization to the behavioural effects of cocaine and to investigate the relationship between the conditioned response and cocaine-induced sensitization. Male mice (C57BL/6J) were first injected over seven successive days with either saline or cocaine at 2.5, 5, 10 or 20 mg/kg s.c., in the testing room. On the test day, 24 h after the last injection, mice from all conditions were challenged with saline in the testing room to test for conditioned cocaine effects. Mice were video-recorded and various behaviours were later scored using a time-sampling technique. Cocaine-elicited orofacial stereotypy was significantly sensitized at the two highest doses and dose-dependently conditioned at the three highest doses. Cocaine-increased locomotion was sensitized at the three highest doses and significantly conditioned at 10 and 20mg/kg. Cocaine-increased sniffing did not change over pretreatment at any dose, and was conditioned only at 10 mg/kg. Cocaine-decreased immobility also did not change over pretreatment at any dose, but was conditioned at 10 and 20mg/kg. Concomitantly, rearing was reduced by cocaine at 10 and 20mg/kg, without sensitization being induced, and it was reduced under saline challenge after 5 mg/kg cocaine, while cocaine-decreased grooming was sensitized at the three highest doses and conditioned at 10 and 20 mg/kg cocaine. There was a positive relation between the size of the conditioned response for orofacial stereotypy and the magnitude of the unconditioned stimulus (the doses), a result conforming to the Pavlovian account of the placebo effect. This could also be concluded from considering the behaviour patterns as components of a unique placebo effect (hyperkinetic syndrome), since orofacial stereotypy, very apparent at 20 mg/kg cocaine, interfered at that dose with the full-blown expression of locomotion and sniffing, both yielding (approximately) inverted U-shaped dose-effect curves. However, no correlation was found between the magnitude of the conditioned response and the amplitude of sensitization (the difference between the initial unconditioned non-sensitized response and the last unconditioned sensitized response), a finding which indicates that conditioned responding does not participate in the generation of the sensitized effects, contrary to the 'excitatory conditioning model of contextual sensitization'.     

Effects of LSD-25 on classical trace conditioning

This study examined the effects of LSD-25 on the excitatory properties of auditory conditioned stimuli as a function of the interstimulus interval. The rabbit's eyeblink response was conditioned using a discriminative trace procedure by the pairing of a 500-msec auditory conditioned stimulus with a 100-msec shock unconditioned stimulus at intervals of 1000, 2000, 4000 and 8000 msec. Animals were able to acquire conditioned responses across all intervals. They then received doses of 35 or 85 micrograms/kg of LSD-25 prior to additional conditioning sessions. LSD-25 produced an increase in the magnitude of conditioned responses to both the positive and negative conditioned stimuli at all interstimulus intervals. It was concluded that LSD did not alter discriminative conditioning but rather enhanced the excitatory properties of both positive and negative conditioned stimuli.     

Short-term contextual sensitisation and conditioned hyperkinesia produced by cocaine in suckling rats aged 4-10 days and 14-20 days

Rationale: Long-term exposure to nicotine is associated with chronic tolerance to its acute effects, adaptation that may lead to tobacco dependence. The time course for loss of this tolerance after cessation of exposure is not known in humans but could relate to risk of smoking relapse. Objectives: We examined changes in responses to nicotine as a function of days, weeks, or years of smoking cessation in formerly dependent smokers to determine at what point sensitivity to nicotine is reinstated (i.e., loss of tolerance). Methods: Acute subjective, cardiovascular, performance, and reinforcing (self-administration) effects of nicotine nasal spray (0–20 μg/kg) were assessed prospectively in men and women smokers before and then day-by-day (study 1) or 3 weeks (study 2) after stopping smoking. A smoking resumption period (study 1) and a group of non-quitting smokers (study 2) were included to control for the passage of time. These effects were also compared cross-sectionally between those who had quit for 1–4 years and those who had for 6–19 years in a separate sample of long-time ex-smokers to determine whether lengthier abstinence causes greater loss of tolerance (study 3). Results: No clear loss of tolerance was observed on any measure in studies 1 or 2, suggesting that chronic tolerance is fully maintained for at least weeks after quitting smoking. Sensitivity to nicotine's effects was also not different as a function of years quit in study 3. Conclusions: Chronic tolerance to nicotine is not lost within several weeks of quitting smoking and may not change even after years of abstinence from tobacco use. Electronic Publication     

Intravenous cocaine-induced activity in A/J and C57BL/6J mice: behavioral sensitization and conditioned activity

The stimulant properties of cocaine have been extensively investigated in the mouse using either intraperitoneal (i.p.) or subcutaneous (s.c.) administration of drug. However, cocaine use in humans often involves intravenous (i.v.) administration of drug. The purpose of this study was to develop a methodology for studying i.v. cocaine-induced activity in the mouse, which allows within-session determination of the dose-response function, and assessment of the development of behavioral sensitization and conditioned activity. The stimulant effects of i.v. cocaine (3-25 mg/kg) were investigated in C57BL/6J and A/J mice both acutely and following repeated treatments (four treatments at 48 hour intervals), in addition to the conditioned activating properties of the cocaine-paired context. Cocaine produced a dose-dependent increase in measures of motor activity in both strains of mice. Repeated cocaine treatments resulted in the development of behavioral sensitization to the stimulant properties of the drug at all doses tested, and exposure to the cocaine-paired context in the absence of drug revealed the development of conditioned activity. While both C57BL/6J and A/J strains displayed these phenomena, differences were observed between ambulation and total beam breaks, highlighting differences between multiple behavioral end-points. Both strains of mice displayed conditioned activity of a higher magnitude than their response to novelty, in addition to a positive relationship between the number of drug-environment pairings and the magnitude of the conditioned response. In summary, these data extend to the i.v. route of administration previous observations on cocaine-induced activity and conditioned activity.     

Differential effects of excitotoxic lesions of the amygdala on cocaine-induced conditioned locomotion and conditioned place preference

The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This type of classical conditioning is of considerable clinical relevance, as intense drug craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. Given the large body of evidence that implicates the amygdaloid complex in the learning of stimulus-reward associations, the present experiments examined the effects of quinolinic acid lesions of the amygdala on cocaine-induced conditional locomotion and conditioned place preference (CPP). Destruction of the amygdala did not affect basal or cocaine-induced locomotion, suggesting that the amygdala does not mediate the unconditioned psychomotor stimulant effects of this drug. Preconditioning lesions also failed to affect cocaine-induced conditional locomotion. Specifically, exposure of both lesioned and non-lesioned rats to a cocaine-paired environment produced significant conditional increases in locomotion. This lack of effect was contrasted by a complete blockade of cocaine-induced CPP by the amygdaloid lesions. These data demonstrate that cocaine-induced stimulus-reward conditioning can be differentially affected by lesions of the amygdala.     

8-OHDPAT effects upon cocaine unconditioned and conditioned behaviors: a role for drug stimulus effects

The effects of the 5-HT1A agonist, (+/-)-8-hydroxy-dipropylaminotetralin (8-OHDPAT) upon the unconditioned and conditioned behavior induced by cocaine were assessed in rats. Separate groups (n=7) received saline, cocaine (10 mg/kg), 8-OHDPAT (0.2 mg/kg), or 8-OHDPAT (0.2 mg/kg) plus cocaine (10 mg/kg) for eight treatment sessions (two per week) in which the rats were tested for 20 min in an open-field. On the eighth treatment session, cocaine enhanced locomotion and rearing but decreased grooming. 8-OHDPAT also decreased grooming and, when given in combination with cocaine, enhanced locomotion but attenuated cocaine-induced rearing. The two 8-OHDPAT groups differed substantially from each other and from the cocaine group in terms of locomotion during the drug treatment phase. Subsequently, all groups received a series of conditioning tests in which they received saline, 0.1, 0.2, or 0.4 mg/kg 8-OHDPAT prior to testing. Groups which had received either 8-OHDPAT or cocaine prior to the conditioning tests exhibited equivalent conditioned effects on the saline conditioning test. When conditioning tests were conducted with 8-OHDPAT, however, only the group which had previously received the combined 0.2 mg/kg 8-OHDPAT plus cocaine treatment exhibited a conditioned response and this effect only occurred at the 0.2 8-OHDPAT dose level. These observations indicate the important influence of the stimulus properties of drugs for the study of drug conditioning and for understanding drug interactions with cocaine.     

Cocaine-induced conditioned taste avoidance over extended conditioned stimulus-unconditioned stimulus intervals

Although long-delay learning has been demonstrated numerous times in the conditioned taste avoidance procedure, the empirical evidence showing this is almost exclusively limited to studies using emetics. Given that compounds outside the emetic class (e.g. drugs of abuse) are also effective in inducing conditioned taste avoidances, the present study assessed the ability of cocaine, a non-emetic psychoactive compound, to support long-delay conditioning as the unconditioned stimulus in conditioned taste avoidance preparation. Using saccharin as the conditioned stimulus, two taste-drug pairings were followed by six extinction trials during which saccharin was presented without subsequent injections of cocaine. During the two conditioning trials, animals were injected subcutaneously with cocaine (32 mg/kg) at different conditioned stimulus-unconditioned stimulus intervals, that is, 10, 60, 120, 180, 240, 300, 420 and 540 min. A control group of animals was given an equi-volume injection of the drug vehicle at the 10-min conditioned stimulus-unconditioned stimulus interval. After two conditioning trials, all treatment groups consumed significantly less saccharin than controls, with the magnitude of the effect decreasing as the conditioned stimulus-unconditioned stimulus interval increased. After six extinction trials, animals injected with cocaine at 10, 60 and 120 min conditioned stimulus-unconditioned stimulus intervals still consumed significantly less than controls. These results with cocaine suggest that taste avoidance learning over long delays is not limited to classical emetic compounds and may, in fact, be characteristic of taste avoidance learning in general.     

Scopolamine inhibits cocaine-conditioned but not unconditioned stimulant effects in mice

RATIONALE: In animal models, cocaine cues contribute to the development of conditioned responses to the psychomotor stimulating and rewarding effects of the drug. OBJECTIVES: In the present study we investigated the effect of scopolamine, known to impair learning and memory, on cocaine-induced conditioned and unconditioned responses in Swiss Webster mice. METHODS: In the first experiment, mice were treated with saline/saline, saline/cocaine (20 mg/kg), scopolamine (1.0 mg/kg)/cocaine, or scopolamine/saline for 5 days. The treatments were paired with the locomotor activity test cage twice, on days 1 and 5. This allowed to determine: (a) the induction and expression of place-dependent sensitization (PDS) to the psychomotor-stimulating effect of cocaine and (b) place-dependent hyperlocomotion (PDH; i.e., conditioning) as defined by the response to saline injection in the test cage. In the second experiment, all injections were delivered in animals' home cage in order to induce place-independent sensitization (PIS) to cocaine and to avoid the development of PDH. In the third experiment, the effect of scopolamine (1.0 mg/kg) on the acquisition of cocaine-induced conditioned place preference (CPP) was investigated. RESULTS: Data from the first experiment suggest that pretreatment with scopolamine had no specific effect on the induction and expression of cocaine-induced PIS. However, scopolamine blocked cocaine-induced PDH. Results from the second experiment confirmed that scopolamine had no effect on the induction of PIS to cocaine. Results from the third experiment showed that scopolamine completely blocked cocaine-induced CPP. CONCLUSIONS: The finding that scopolamine blocked the conditioned behaviors, PDH and CPP, that develop after exposure to cocaine supports the hypothesis that cocaine cue reactivity in the paradigms tested is associated with learning and memory.     

Classically conditioned motor effects do not occur with cocaine in an unbiased conditioned place preferences procedure

Classical conditioning and behavioural sensitisation of motor activity induced with cocaine (10mg/kg, i.p.) were examined using an unbiased two-compartment conditioned place preference (CPP) procedure. Habituation of the rats to the testing environment prior to training was varied (i.e. either the rats were habituated to the environment for three 30min sessions or they were not) in order to examine a possible influence of latent inhibition on conditioned locomotion or behavioural sensitisation. Furthermore, rats were either trained with an explicit CS+ (cocaine-paired compartment) and CS- (vehicle-paired compartment), or else they were trained with no barrier between the compartments (effectively a single-compartment procedure with no explicit CS-) in order to examine a possible influence of stimulus change (training rats while confined to one compartment, but testing with no barrier between compartments). On a drug-free test day with free access to both compartments, rats previously exposed to cocaine in one compartment (CS+) and vehicle in the second compartment (CS-) spent more time in the CS+ compartment (conditioned place preference). However, under no circumstance was the rate of motor activity higher in the CS+ compartment than in the CS- compartment, as would be expected if cocaine-induced motor activity was classically conditioned to contextual cues. Whether or not increased activity extinguished with repeated drug-free exposures to previously drug-paired contexts depended on habituation experience. In addition, both habituation and current access to compartments (free or restricted) determined the presence of post-extinction sensitisation to a challenge dose of cocaine (7.5mg/kg). Classical conditioning and non-associative sensitisation, independently or together, cannot account for this pattern of results.     

Conditioned locomotion is not correlated with behavioral sensitization to cocaine: an intra-laboratory multi-sample analysis.

Pre-clinical and clinical studies have demonstrated the importance of associative factors in regulating craving for drugs of abuse. To model these conditioned effects, we have examine cue-induced conditioned locomotion in rodents. The present study involved analysis of several of our prior studies to evaluate the relationship between conditioned locomotion and behavioral sensitization using a within-subjects analysis. Both are animal models used to study addiction, so it is important to know if one is predictive of the other, and more generally, if drug effects are predictive of conditioned effects. In all of our studies, Paired subjects received cocaine during presentation of conditioned stimuli while Unpaired subjects received saline with the stimuli and cocaine at the home cages an hour later. Paired subjects typically displayed behavioral sensitization over the course of training. After the completion of training, all subjects were tested with the conditioned stimuli in the absence of drug and conditioned locomotion was measured. The response of Unpaired subjects on the last training day was positively correlated with their response on test day, as expected since both days were nearly identical (stimuli presented without cocaine). However, for Paired subjects, the magnitude of conditioned locomotion on the drug-free test day was not positively correlated with the magnitude of behavioral sensitization. These results underscore the importance of focusing research on drug-free conditioned behaviors when attempting to model conditioned responses to drug related cues in human addicts.     

Chronic cocaine pretreatment facilitates Pavlovian sexual conditioning in male Japanese quail

Repeated drug exposure that results in behavioral sensitization has been shown to enhance sex-seeking behaviors in rats as well as facilitate Pavlovian excitatory and inhibitory conditioning. In the present experiment, male Japanese quail were given repeated presentations of cocaine (10 mg/kg, i.p.) that resulted in increased locomotor activity relative to saline. After a 10-day withdrawal period, subjects received sexual conditioning trials that consisted of presentation of an object conditioned stimulus (CS) followed by sexual reinforcement. Results showed that birds that previously received chronic cocaine demonstrated more conditioned approach behavior to the CS object, a shorter latency to copulate with a female, and made more cloacal contacts (copulatory behavior) during sexual reinforcement than saline-treated birds. The findings suggest that chronic cocaine later facilitates Pavlovian conditioning in a sexual behavior paradigm. This may be the result of cocaine facilitating learning via the dopaminergic system. The findings are discussed in the context of the incentive sensitization theory and possible neuronal mechanisms.     

Dissociation of Novelty- and Cocaine-Conditioned Locomotor Activity From Cocaine Place Conditioning

High locomotor response to novelty is associated with ease of drug self-administration but does not predict greater place-conditioning effects of drugs. Yet, the latter reflects context conditioning and high responders (HR), compared to low responders (LR), show greater conditioned locomotor effects. Conditioned locomotor effects may occur in place conditioning, perhaps confounding its measure. To examine whether conditioned locomotor effects occur in place conditioning, the present study classified rats as HR vs. LR by using approximately the two extreme 15% percentiles of the distributions. The place conditioning and locomotor sensitizing effects of cocaine were tested. In Experiment 1, HR rats exhibited more crossings between compartments but did not differ from LR rats in cocaine place conditioning. Further, both groups showed increased crossings at test compared to baseline, indicative of a conditioned locomotor effect. In Experiment 2, HR rats showed greater acute locomotor activation to cocaine, whereas LR rats tend to show greater locomotor sensitization. Finally, in Experiment 3, HR rats showed habituation in locomotor responses, whereas LR rats did not. Results of these studies suggest that inherent and conditioned locomotor activity levels are dissociated from place-conditioning effects.     

Response to novelty as a predictor of cocaine sensitization and conditioning in rats: a correlational analysis

Rationale An animal's response to novelty has been suggested to be a predictor of its response to drugs of abuse. The possible relationship between an individual's behavioral response to novelty and its subsequent behavioral response to cocaine has not been subjected to a detailed correlational analysis. Objective To use a repeated cocaine treatment protocol to induce cocaine sensitization and conditioned cocaine locomotor stimulant effects and to assess the relationship of these effects to pre-cocaine locomotor behavior in a novel environment. Methods In two separate experiments, rats were given a 20-min test in a novel open-field environment. Subsequently, the rats were given a series of additional tests in conjunction with either saline or cocaine (10 mg/kg) treatments to induce cocaine sensitization and conditioned effects. Results The repeated cocaine treatments induced cocaine behavioral sensitization and conditioned effects. Correlational analyses showed that the initial 20-min novel environment test proved to be a strong predictor of an animal's subsequent saline activity level but did not predict the rats' behavioral acute and sensitized response to cocaine. When change in activity was used as the dependent variable, initial activity level was reliably negatively correlated with activity changes on cocaine tests as well as cocaine conditioning tests. Conclusions The negative correlation between initial activity in a novel environment and the change in activity induced by cocaine indicates that low responders to environmental novelty tend to have the strongest response to cocaine. These results appear consistent with the classic initial value and response rate dependent analyses of stimulant drug effects.     

Conditioned locomotion in rats following amphetamine infusion into the nucleus accumbens: blockade by coincident inhibition of protein kinase A

Recent studies demonstrate a role for cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) in the nucleus accumbens (NAc) in reward-related learning. To clarify this role, we assessed the effect of PKA inhibition on the unconditioned and conditioned locomotor activating properties of intra-NAc amphetamine. Rats underwent three 60 min conditioning sessions, pairing a test environment with bilateral co-infusions of amphetamine (25 microg/side) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) (0, 2.5, 250, 500 ng, 1, 10 or 20 microg/side). Two additional groups - receiving amphetamine explicitly unpaired with the environment or saline/environment pairings - served as controls. In a subsequent drug-free 60 min session, animals that received amphetamine/environment pairings demonstrated conditioned locomotion relative to controls. Rp-cAMPS co-treatment during pairing sessions differentially affected conditioned and unconditioned locomotor activation. Amphetamine-induced unconditioned activity was significantly enhanced by 500 ng and 1 microg Rp-cAMPS, locomotor sensitization was enhanced by 250 ng-1 microg Rp-cAMPS, and conditioned activity was attenuated by 1 microg Rp-cAMPS and blocked by 10 and 20 microg Rp-cAMPS. Thus, unconditioned activity and locomotor sensitization were enhanced at doses (250 ng-1 microg) that did not affect or attenuated conditioned activity, while conditioned activity was reduced or blocked at doses (1-20 microg) that enhanced or did not affect overall unconditioned activity. These results demonstrate that the activation of PKA plays a critical role in the process by which properties of drugs become associated with environmental stimuli.     

Cocaine-induced behavioral sensitization and conditioning in male Japanese quail

Repeated intermittent cocaine treatment often results in behavioral sensitization or an augmented response to cocaine. Cocaine-induced behavioral sensitization may be an important contributor to cocaine addiction and abuse. Some studies have also shown that conditioned drug effects may play a role in behavioral sensitization. The current experiment utilized a simplified discrimination paradigm to investigate behavioral sensitization and the role of conditioning in an avian species. Male Japanese quail received alternating injections of cocaine (10 mg/kg i.p.) paired with a context and saline injections paired with a different context. They were later given a cocaine challenge followed by and a saline challenge in the drug-paired context. Results showed that birds that received cocaine paired with one context also demonstrated behavioral sensitization to a cocaine challenge given after a withdrawal period and they developed conditioning to the drug-paired context. A saline control and a control group that received cocaine that was not paired with the test context failed to demonstrate sensitization or conditioning. The findings demonstrate visual discrimination learning and implicate the role of Pavlovian conditioning in behavioral sensitization.     

Susceptibility to morphine place conditioning: relationship with stress-induced locomotion and novelty-seeking behavior in juvenile and adult rats

Previous studies demonstrated that the rewarding effect of psychostimulants, such as amphetamine and cocaine, can be predicted by locomotor activity toward novelty in a free-choice situation but not motor response developed in inescapable environment. However, whether this relationship also exists with narcotic morphine remains unclear. In the present study, the relationship between morphine place conditioning and open field as well as novelty-seeking behavior was examined in both juvenile and adult rats. By using arena open field and the same arena containing novel object, we investigated the initial open-field activity and novelty-seeking behavior after familiarization process, respectively, in juvenile and adult rats. Subsequently, the relationship between morphine (2 mg/kg) place conditioning and the above two behaviors was examined. Our results demonstrated that morphine place conditioning effect was readily acquired in both groups. The magnitude of this effect positively correlated with novelty-seeking intensity but not with open-field activity. This is the case whether juvenile or adult group was examined separately or across ages. However, only rats with high response to novelty (NHR) from their respective group expressed significant duration increase in drug-paired compartment. Rats with low response to novelty (NLR) showed no sign of this effect after the same drug training, suggesting slow acquisition of this effect in NLRs. These results also indicated that novelty-seeking actions and the rewarding effect of morphine possessed a common pathway and that neural and hormonal substrates activated in a mild stress environment like in the open field may not be critically involved in this process. The ontogenetic specificity and nonspecificity between different-aged rats as with the above relationship were discussed in this paper.     

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

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

Conditioned slowing of stomach emptying produced by Pavlovian pairings of a drug CS or a place with lithium chloride

Lithium chloride, in common with other drugs with emetic effects, prolongs stomach emptying. In different experiments, a drug state induced by a low dose of pentobarbital in Experiment 1 and morphine in Experiment 2 or a distinctive place (Experiments 3, 4) was the conditioned stimulus paired with lithium chloride as the unconditioned stimulus. In each case, Pavlovian conditioning occurred and the conditioned response mimicked lithium's unconditioned effect on stomach emptying.     

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.     

Nimodipine and haloperidol attenuate behavioural sensitization to cocaine but only nimodipine blocks the establishment of conditioned locomotion induced by cocaine

The classical conditioning of the behavioural effects of cocaine has been shown to contribute to behavioural sensitization. In the present experiments, it was demonstrated that the effects of cocaine in rats can be conditioned to contextual stimuli. Furthermore, sensitization to cocaine's locomotor effects were demonstrated, and shown to be context specific. Nimodipine (10 mg/kg, SC), an L-type dihydropyridine Ca²⁺ channel antagonist, appeared to completely block the establishment of conditioning of cocaine's effects, but only partially blocked sensitization to cocaine. Haloperidol (0.05 mg/kg, IP), a relatively specific D₂ dopamine receptor antagonist, attenuated behavioral sensitization but had no influence on the establishment of the conditioned component of cocaine. These results indicate that the sensitization to, and the development of classical conditioning of, cocaine's behavioural effects can be pharmacologically dissociated, but that a non-associative process involved in sensitization is normally overridden by conditioning factors.