Effects of beta-funaltrexamine and naloxonazine on single-trial morphine-conditioned place preference and locomotor activity

The current study assessed the ability of the selective irreversible mu-opioid receptor antagonists beta-funaltrexamine (betaFNA) and naloxonazine (NALZ) to alter the locomotor and rewarding effects of a single intravenous injection of morphine using the conditioned place preference (CPP) model. In the first experiment, rats were conditioned with a single injection of morphine (10 mg/kg iv) paired with one compartment of a CPP apparatus and then were tested for CPP at either 1 or 7 days after conditioning. Rats showed hypoactivity following acute morphine on the conditioning trial and showed CPP when tested either 1 or 7 days later. In the next experiments, rats were pretreated with betaFNA (20 mg/kg sc, 20 h before conditioning), NALZ (15 or 30 mg/kg sc, 24 h before conditioning) or saline and then were conditioned with a single injection of morphine (10 mg/kg iv) or saline. Pretreatment with NALZ alone, but not betaFNA, significantly decreased locomotor activity; neither antagonist alone produced a significant shift in preference for either compartment of the CPP apparatus. Pretreatment with either betaFNA or NALZ blocked completely morphine-induced hypoactivity, but neither antagonist had a significant effect on morphine CPP. These results indicate that mu-opioid receptors are more critically involved in acute morphine-induced hypoactivity than in acute morphine reward.     

Dynorphin A (2–17) attenuates the unconditioned but not the conditioned effects of opiate withdrawal in the rat

OBJECTIVES: An unbiased place preference conditioning procedure was used to examine the influence of the non-opioid peptide, dynorphin A 2-17 (DYN 2-17), upon the conditioned and unconditioned effects of opiate withdrawal in the rat. METHODS: Rats were implanted SC with two pellets containing 75 mg morphine or placebo. Single-trial place conditioning sessions with saline and the opioid receptor antagonist naloxone (0.1-1.0 mg/kg; SC) commenced 4 days later. Ten minutes before SC injections, animals received an IV infusion of saline or DYN 2-17 (0.1-5.0 mg/kg). Additional groups of placebo- and morphine-pelleted animals were conditioned with saline and DYN 2-17. During each 30-min conditioning session, somatic signs of withdrawal were quantified. Tests of place conditioning were conducted in pelleted animals 24 h later. RESULTS: Naloxone produced wet-dog shakes, body weight loss, ptosis and diarrhea in morphine-pelleted animals. Morphine-pelleted animals also exhibited significant aversions for an environment previously associated with the administration of naloxone. These effects were not observed in placebo-pelleted animals. DYN 2-17 pretreatment resulted in a dose-related attenuation of somatic withdrawal signs. However, conditioned place aversions were still observed in morphine-pelleted animals that had received DYN 2-17 in combination with naloxone. Furthermore, the magnitude of this effect did not differ from control animals. CONCLUSIONS: These data demonstrate that the administration of DYN 2-17 attenuates the somatic, but not the conditioned aversive effects of antagonist-precipitated withdrawal from morphine in the rat. Differential effects of this peptide in modulating the conditioned and unconditioned effects of opiate withdrawal are suggested.     

Caffeine-induced place and taste conditioning: production of dose-dependent preference and aversion

Although caffeine may be the most widely used behaviorally active drug, few studies have examined its rewarding properties. In the present study, the designs of place-conditioning and taste-conditioning paradigms were combined in a single experiment to provide two independent measures of drug reward. During 3 preconditioning sessions, undrugged rats received access to 2 distinctive chambers connected by a small tunnel. During the 8-session conditioning phase, groups were given home cage access to either a sweet or salty solution, administered caffeine (0.3, 1.0, 3.0, 10.0, 30.0 mg/kg IP; 30.0 mg/kg SC), and confined to one of the chambers. On alternate sessions, rats were given home cage access to the remaining solution, injected with the vehicle, and confined to the opposite chamber. On test sessions 1 and 2, undrugged animals were given home cage access to one of the flavored solutions and water, and then allowed access to both conditioning chambers. On test session 3, rats were given access to both flavored solutions, injected with the drug used during conditioning, and again allowed access to both chambers. Caffeine (3.0 mg/kg) produced a significant place preference. The highest dose (30.0 mg/kg IP and SC) produced significant place and taste aversions. A control group given (+)-amphetamine illustrated a significant place preference and taste aversion as expected. Thus caffeine appeared to produce a dose-dependent biphasic effect; a lower dose was rewarding, whereas higher doses produced aversions to environmental stimuli associated with the drug.     

Conditioned suppression with cocaine as the unconditioned stimulus

A conditioned-suppression procedure was used to study drug conditioning using cocaine as the unconditioned stimulus (UCS). Rats were first trained to nose poke for food-reinforcement during daily 60-min sessions. At least 1 week following jugular vein catheterization, a 5-min tone-light compound stimulus was presented 30 min into the food-reinforcement session. Two minutes after the onset of the stimulus, either 0 (saline), 1.0, 3.0 or 5.6 mg/kg cocaine, was administered i.v. to separate groups of rats. For another group, the stimulus was presented, and the 5.6 mg/kg dose of cocaine was injected in an unpaired fashion (i.e., at different times). After 5 days of training a test was given with the tone-light stimulus presented alone. No disruption of responding during the tone-light stimulus was observed in the saline and 1.0 mg/kg cocaine groups or for the unpaired group. When the tone-light stimulus was paired with 5.6 mg/kg cocaine; however, it produced nearly a 50% reduction in responding, which then gradually extinguished when the stimulus was presented alone for 5 days. The 3.0 mg/kg cocaine group produced intermediate suppression. When the tone-light compound stimulus was shortened to 70 s and the interstimulus interval (ISI) was 0, 30, or 60 s in three separate groups of rats, the most robust conditioned suppression was observed at the 60 s ISI. Therefore, the conditioned suppression procedure, using 3.0 or 5.6 mg/kg i.v. cocaine doses as the UCS, produced robust conditioning effects comparable to other drugs and more conventional reinforcers. The conditioned suppression procedure may be a useful model for studying the classically conditioned effects of cocaine.     

The differential role of A1 and A2 adenosine receptor subtypes in locomotor activity and place conditioning in rats

Previous studies have demonstrated that the non-specific adenosine antagonist caffeine possesses both motor activating and rewarding properties in a place-conditioning paradigm. The present experiments were designed to determine the relative contribution of A1 and A2 adenosine receptor subtypes to these effects. The A2 adenosine antagonist CGS 15943A (0.1-10.0mg/kg) dose-dependently produced both a place preference and enhanced locomotor activity. In contrast, the A1 antagonist CPX (0.01-40.0mg/kg) failed significantly to alter either behavioral measure. Both the A1 receptor agonist CPA (0.01-10.0mg/kg) and the A2 receptor agonist CGS 21680 (0.01-1.0mg/kg) reliably decreased activity but failed to produce significant place conditioning. The increased activity produced by the A2 antagonist CGS 15943A (1.0mg/kg) was attenuated by behaviourally active doses of either CPA or CGS 21680. The place preference produced by CGS 15943A (1.0mg/kg) was attenuated by CPA and CGS 21680, at agonist doses that failed to produce place conditioning when administered alone. In general, the results suggested that although it is the A2 receptor subtype that participates in the establishment of place conditioning and enhanced activity, both receptors participate in the diffuse depressant effects associated with adenosine.     

Selective D1 and D2 dopamine agonists produce opposing effects in place conditioning but not in conditioned taste aversion learning

The neurotransmitter, dopamine (DA), has been implicated in place conditioning but the role of D1 and D2 receptors has not been investigated. In Experiment 1, the effects of SKF 38393 (0, 0.01, 0.1, 1.0, 10.0 mg/kg) and quinpirole (0, 0.01, 0.1, 1.0, 2.0, 4.0 mg/kg), preferential D1 and D2 receptor agonists, respectively, were evaluated and compared to (+)-amphetamine (0, 0.01, 0.1, 1.0, 2.0, 4.0 mg/kg). The experiment consisted of three phases. During the preexposure phase, rats explored two distinctive end compartments adjoined by a small tunnel. The time spent in each compartment was recorded. During the 8-day conditioning phase, rats were treated with drug and confined to one compartment for 30 min. On alternate days, rats received saline and were placed in the opposite compartment. Test days occurred over the remaining three days during which drug-free animals explored both compartments. Rats conditioned with (+)-amphetamine demonstrated a dose-dependent increase in time spent in the drug-paired environment from preexposure to test indicating the establishment of a conditioned place preference. Treatment with quinpirole also resulted in a conditioned place preference, however, only an intermediate dose was effective. In contrast, SKF 38393 produced a dose-dependent decrease in time spent on the drug-paired side suggesting the establishment of a place aversion. The idea that D1 receptors may be exclusively involved in mediating the aversive properties of psychomotor stimulants was tested in Experiment 2 employing a conditioned taste aversion paradigm. The results did not support this notion; it was found that both quinpirole and SKF 38393 produced a conditioned taste aversion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brief exposure to a mild stressor enhances morphine-conditioned place preference in male rats

Rationale Exposure to moderate tail shock [3, 0.75 s, 1 mA, 20 s interstimulus interval (ISI)] can enhance pain reactivity (hyperalgesia) in rats. This hyperalgesia reflects an unconditioned response that transfers across contexts and is associated with enhanced Pavlovian fear conditioning to aversive unconditioned stimuli (US). It is possible that moderate shock also enhances learning about appetitive stimuli such as a reinforcing drug.Objectives The present study examined the effect of moderate shock exposure on unconditioned psychomotor activation and appetitive conditioning using a morphine place-preference task.Methods During training, rats were given moderate shock or restraint and then received subcutaneous morphine at one of four doses (0.0, 0.2, 1.0, or 5.0 mg/kg) and were transferred to a conditioning apparatus. Five hours later, animals were given discrimination training in a different context. Animals received 2 days of training, each separated by a day of testing for preference. To test the impact of shock on psychomotor activation, subjects were given shock or restraint and one of two doses of morphine (0.0 mg/kg or 5.0 mg/kg) and placed in a box to monitor activity.Results Vehicle-treated shocked rats showed a conditioned place aversion. Subjects that received morphine showed a dose-dependent place preference that was facilitated by moderate shock exposure. Shock also enhanced the motor activation produced by morphine.Conclusions These results indicate that the affective state produced by moderate shock has a negative valence that is sufficient to support a conditioned place aversion. This state is associated with a general sensitization that enhances processing of appetitive US.     

The rewarding properties of NMDA and MK-801 (dizocilpine) as indexed by the conditioned place preference paradigm.

N-Methyl-D-aspartate (NMDA) ([R]-2-[Methylamino]succinic acid) is a specific excitatory amino acid. Two experiments were conducted to determine the rewarding properties of this compound using the conditioned place preference paradigm. In the first experiment, 40 male Sprague-Dawley rats received place preference conditioning for a 4 day period. The conditioned place preference apparatus consisted of two chambers with distinct visual and tactile cues, separated by a removable door. On days 2 and 4, rats were systemically administered NMDA (1.0, 15.0, and 30.0 mg/kg) paired with one chamber. On days 3 and 5, rats were systemically administered saline paired with the other chamber. Day 6 was the test day, and the rat was allowed free run of the entire apparatus in a drug-free state. Time spent in each side of the apparatus was computer recorded. NMDA produced a significant increase in the amount of time spent on the side previously paired with drug for 15.0 and 30.0, but not 1.0 mg/kg NMDA. In the second experiment, systemic administration of NMDA (30.0 mg/kg) paired with the noncompetitive NMDA receptor antagonist, MK-801 (0.5 mg/kg), resulted in neither place preference nor place aversion.     

Effects of selective drugs for dopaminergic D1 and D2 receptors on conditioned locomotion in rats

Classically conditioned locomotor activity has been demonstrated by pairing injections of dopamine agonists or antagonists with specific environmental stimuli. The present studies investigated conditioning using drugs with varying selectivity for the dopamine D1 or D2 receptor. Experiment 1 assessed conditioning in groups of rats using the indirect acting agonist (+)-amphetamine (2.0 mg/kg), and the D1 agonist SKF 38393 (10.0 mg/kg), the D2 agonist quinpirole (2.5 mg/kg), the D1 and D2 antagonists, SCH 23390 (0.05 mg/kg) and metoclopramide (25.0 mg/kg), respectively. Paired groups received nine 2-h drug-environment (automated activity monitoring chambers) pairings whereas Unpaired groups received the stimuli explicitly unpaired. Test revealed conditioned hyperactivity with each agonist and metoclopramide whereas conditioned hypoactivity was seen with SCH 23390. Experiment 2 assessed the interaction of these agonists and antagonists on the establishment of conditioned activity. Paired groups received an agonist and antagonist during conditioning sessions. SCH 23390 blocked conditioning based on (+)-amphetamine and SKF 38393 but not quinpirole. Metoclopramide (10.0 mg/kg) blocked conditioning based on quinpirole but not SKF 38393. Metoclopramide (25.0 mg/kg) also did not block (+)-amphetamine-induced conditioning. These studies suggested that drug-induced alterations at either D1 or D2 receptors may be involved in conditioned locomotion.     

Behavioral interactions between nicotine and caffeine

Nicotine (0.01-1.0 mg/kg) was administered alone and together with three doses of caffeine (3.0, 10.0 and 30.0 mg/kg) to rats responding on a fixed-interval 2-min schedule of food reinforcement. The effects on overall response rate depended on dose: with the 3.0 mg/kg dose of caffeine response rate was increased by an amount approximately equal to the effect of the caffeine alone, while 10.0 mg/kg of caffeine reduced and 30.0 mg/kg completely abolished the increases in response rate produced by nicotine. The within-interval pattern of responding was affected in a similar, dose-related manner by both nicotine and caffeine alone. These effects added to produce large changes in the pattern when high doses of the two drugs were co-administered. The changes comprised increases in lower response rates in the early and middle parts of the interval and proportionally smaller increases or decreases in the higher rates occurring later in the interval. The interaction between nicotine and caffeine cannot be characterized simply, but depends on the particular aspect of behavior under examination.     

Sex differences in locomotor activity after acute and chronic cocaine administration.

Adult, intact and gonadectomized male and female Wistar rats (n = 9) were exposed to an automated open field to assess the behavioral effects of acute cocaine administration (saline, 1.0 and 10.0 mg/kg subcutaneous). The subjects were exposed to the open field for 10 min, removed to be injected and returned to the open field for another 30 min. Three saline and two drug sessions were run in counterbalanced order. Locomotor activity in intact and castrated male rats and ovariectomized female rats decreased following injection, irrespective of the dose of cocaine. The locomotor activity of intact female rats was higher than that of any other group of subjects. It decreased during the session after saline and 1.0 mg/kg cocaine, but increased towards the end of the 30 min session after 10.0 mg/kg. Rearing measures paralleled the observations on locomotor activity. To determine the effects of chronic, home-cage, cocaine administration, five of the subjects in each group were injected with 10.0 mg/kg cocaine for 9 consecutive days. The remaining four subjects received saline injections. On day 10, all subjects were re-exposed to the open-field for 10 min, removed, injected with 10.0 mg/kg cocaine and returned to the open field for another 30 min. Chronic home cage cocaine administration produced an increase in cocaine's effects on locomotor activity and rearing in intact female rats only. However, behavioral sensitization was also observed in intact female rats who had been treated with saline for 9 consecutive days, suggesting that behavioral sensitization to cocaine in intact female rats may develop very rapidly and independent of environmental context.     

Sex differences in tolerance to the locomotor depressant effects of lobeline in periadolescent rats

Lobeline is being tested in clinical trials as a pharmacotherapy for methamphetamine abuse and attention deficit hyperactivity disorder. Preclinical research demonstrates that lobeline produces locomotor hypoactivity apart from its therapeutic effects; however, the hypothesis that there are sex differences in hypoactivity or in the development of tolerance to its locomotor depressant effects has not been investigated. Periadolescent rats were injected with saline to determine baseline locomotor activity. Animals received saline or lobeline (1.0–10 mg/kg) daily for 7 consecutive days (post natal days 29–35), and were challenged with saline 24 h later to assess baseline activity. Lobeline produced hypoactivity in total horizontal activity and center distance travelled. Tolerance developed to the lobeline-induced hypoactivity and sex differences in lobeline tolerance were observed on both measures. Females acquired tolerance to lobeline 5.6 mg/kg at a slower rate than males. Saline challenge revealed a linear dose-dependent trend of hyperactivity on both measures, which indicates that rats exhibited altered locomotor behavior 24 h after the final lobeline treatment. These findings demonstrate sex differences in the hypoactive response to lobeline prior to puberty and suggest that females may experience more locomotor depressant effects than males. Chronic lobeline may induce hyperactivity following cessation of treatment.     

Differential effects of dopamine antagonists on locomotor activity, conditioned activity and conditioned place preference induced by cocaine in rats

Neuronal substrates that mediate the conditioned effects of cocaine have not been well characterized. To examine dopaminergic mechanisms, three antagonists were tested for their capacity to inhibit the expression of conditioned locomotor activity and conditioned place preference in rats. Antagonists were also assessed against acute cocaine-stimulated locomotor activity for comparison. For locomotor activity conditioning, six conditioning sessions were conducted over a 10-day period. Paired rats received 10 mg/kg cocaine prior to activity sessions and saline after; unpaired controls received saline prior and cocaine after. For place preference conditioning, eight conditioning sessions were conducted over a 13-day period; rats received 10 mg/kg cocaine while restricted to one of two distinct chambers and, on alternate days, they received saline in the other. Antagonists (haloperidol, raclopride and SCH23390; 0.03-0.1 mg/kg) were given only on test days for conditioned effects. All three antagonists significantly and dose-dependently attenuated the direct stimulatory effect of cocaine. SCH23390 showed a tendency to reduce the expression of conditioned locomotor activity, and only haloperidol blocked the expression of conditioned place preference. Thus, direct and conditioned stimulant effects of cocaine were shown to be differentially sensitive to dopamine receptor blockade. Further, conditioned stimulant effects differed from conditioned reinforcing effects in this regard.     

Extinction procedures abolish conditioned stimulus control but spare sensitized responding to amphetamine

The effect of extinction on previously established environment-specific sensitization of the locomotor activating effects of 1.0mg/kg d-amphetamine sulfate was studied in an attempt to investigate the relation between sensitization and conditioning of the drug effect. During the conditioning phase, groups of eight rats each were administered drug, i.p., prior to being placed in activity boxes and saline in their home cages (paired group), drug in the home cages and saline in the activity boxes (unpaired group), or saline in both environments. Evidence for conditioning and environment-specific sensitization was found following the conditioning phase in tests during which animals were administered saline or amphetamine, respectively. On a final test for environment-specific sensitization that followed the extinction phase (during which all animals received saline injections in both the activity boxes and the home cages), sensitized responding to amphetamine was found in both the paired and unpaired groups, suggesting that prior to extinction the expression of sensitization in the unpaired group had been under inhibitory control.     

Effects of chronic caffeine pre-exposure on conditioned and unconditioned psychomotor activity induced by nicotine and amphetamine in rats

Three experiments examined the effects of chronic pre-exposure to caffeine on the subsequent conditioned and unconditioned locomotor activating effects of nicotine or amphetamine in rats. Rats were given daily intraperitoneal injections of caffeine anhydrous (0, 10 or 30 mg/kg base) for 30 days. Conditioning (environment-drug pairings) began after the last day of caffeine pre-exposure. Pre-exposure to 30 mg/kg of caffeine enhanced the acute and chronic locomotor effects of amphetamine (0.5 mg/kg). A similar enhancement of activity was not seen with the high (0.421 mg/kg base) or low dose (0.175 mg/kg) of nicotine. In a drug-free test, the distinct environment paired with amphetamine and the high dose of nicotine evoked increases in activity relative to controls. Caffeine pre-exposure did not affect expression of this conditioned hyperactivity. These effects of caffeine pre-exposure on amphetamine-induced activity could not be attributed to non-specific effects of caffeine.     

Effects of environmental conditioning on the development of nicotine sensitization: behavioral and neurochemical analysis

We have investigated the effects of environmental conditioning on the induction of nicotine sensitization of locomotion, stereotypy and nucleus accumbens dopamine release. Sprague-Dawley rats, some of which had been previously implanted with a microdialysis guide cannula over the nucleus accumbens, were sensitized with 5 days of repeated nicotine (0.6 mg/kg per day, SC) or saline injections (1 ml/kg per day). During nicotine treatment the drug administration was either paired with the microdialysis/activity monitor testing chamber (conditioned) (n=6) or with the animal's home cage (unconditioned) (n=6) and after 60 min the animal was returned to home cage and received a second injection of saline 15 min later. A third group received saline in the testing apparatus followed by nicotine in the home cage (pseudo-conditioned) (n=6). In the guide cannulated animals, 2 mm microdialysis probes were inserted after completing day 5 of treatment and all animals were tested for their response to nicotine (0.6 mg/kg, SC) on day 6. Both locomotor activity and nucleus accumbens dopamine release showed a larger response subsequent to nicotine challenge in the nicotine versus saline pretreated animals in the conditioned group, but not in the unconditioned group. In the pseudo-conditioned group there was an increase in the stereotypy responses to nicotine, however the locomotor and dopamine release responses were not significantly enhanced. The results from the conditioned group were confirmed in animals which were tested for behavioral activation and dopamine release simultaneously (n=5). These findings indicate that nicotine sensitization of locomotor activity and nucleus accumbens dopamine release (using a 5-day pretreatment protocol) is dependent on conditioning the animal to the testing environment during nicotine pretreatment.     

Conditioned behavioural responses to apomorphine: extinction and haloperidol-induced inhibition

Summary In previous studies it was established that stereo-typies (sniffing, licking, gnawing) produced by apomorphine can be conditioned and after repeated pairings with defined conditioned stimuli (auditory, tactile + olfactory) these stereotypies can be observed in the presence of the conditioned stimuli alone. In the present experiments, the extinction of these conditioned stereotypies was studied in one series; in another series, the possible inhibition of conditioned stereotypies by the blocker of dopamine receptors, haloperidol, was measured. The rats were conditioned (or the controls pseudoconditioned, respectively) for either 3 or 10 days with 2.0 mg/kg s. c. apomorphine or 6 days with 0.5 mg/kg s. c. of the drug and by placing them into particular cages in the presence of an auditory and an olfactory stimulus. Under all these conditions, episodes of conditioned stereotypies were observed, when solvent + conditioned stimuli instead of apomorphine was applied 1 day after the last conditioning session (first session of extinction). The conditioned responses seemed to be on the highest level after conditioning with 2.0 mg/kg apomorphine 3 days, lower after conditioning with the same dose on 10 days, and even lower after conditioning for 6 days with 0.5 mg/kg. Under all these conditions, the stereotypies summed up and averaged for the total observation period of 60 min rapidly decreased during the extinction period, so that on day 4 of the extinction period, no further significant differences between conditioned and pseudoconditioned animals were observed, although a short initial period was still observed on the fourth day. On day 3 of extinction, not only an early, but also a late episode of conditioned stereotypies was manifest, interrupted by an almost silent period. The acute (unconditioned) stereotypies produced by 0.5 mg/kg s. c. apomorphine were almost completely suppressed by pre-treatment with 0.1 mg/kg i. p. haloperidol. In contrast, the same dose of haloperidol produced a much less pronounced inhibition of conditioned stereotypies after conditioning with the same dose of apomorphine for 6 times. These results, together with previous findings, suggest that the conditioned behavioural effects are not due to an activation of dopaminergic mechanisms during conditioning with apomorphine. Send offprint requests to K. Kuschinsky at the above address     

Postconditioning effects of magnesium on cocaine conditioned place preference in mice

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

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'.     

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.