Pavlovian conditioning between co-administered drugs: elicitation of an apomorphine-induced antiparkinsonian response by scopolamine

Sprague-Dawley rats with unilateral 6-OHDA substantia nigra lesions were given combined scopolamine (0.5 mg/kg IP) and apomorphine (0.05 mg/kg SC) treatments. In this animal model, scopolamine, when administered separately, induces ipsilateral rotation and apomorphine, contralateral rotation. When these drugs are co-administered at 0.5 mg/kg and 0.05 mg/kg dose levels, respectively, animals rotate in the contralateral direction, creating the opportunity for the stimulus effect of scopolamine to become associated with the response effect of apomorphine. In tests with scopolamine (0.5 mg/kg), animals that previously had scopolamine and apomorphine co-administered rotated contralaterally in the test chamber, thereby behaving as if they had received apomorphine. Thus, scopolamine exhibited a functionally acquired conditioned stimulus (CS) property by eliciting the apomorphine response of contralateral rotation as a conditioned response. This acquired CS property was extinguished with separate scopolamine trials and reacquired following one scopolamine-apomorphine co-administration trial.     

Studies on interactions between conditioned and unconditioned behavioural responses to apomorphine in rats

Summary Interactions between the direct (unconditioned) behavioural effects apomorphine and its conditioned effects after pairing with previously neutral stimuli were studied. Rats were injected once daily for 3–12 times, with apomorphine (2.0 mg/kg or 0.5 mg/kg or 0.07 mg/kg s.c. the dose kept constant in each series), in the presence of defined environmental stimuli (a wire cage in association with an acoustic and an olfactory stimulus) as conditional stimuli. The two larger doses produced stereotyped sniffing, licking, and gnawing, the smallest dose akinesia, ptosis, yawning and penile erections. During the conditioning phase, the drug produced most of the effects with increasing intensity and in the case of the stereotypies, there also was a shift to higher scores of stereotypy, with a reduced latency in onset of the signs. On the test day, 1 day after the last administration of apomorphine, the conditioned rats as well as pseudoconditioned controls were treated with a test dose of apomorphine in the presence of the conditional stimuli. Pseudoconditioned rats had been treated with the same pharmacological schedule of apomorphine and had the same familiarity with the stimuli, but both were kept separate. A test dose of 0.5 mg/kg of apomorphine produced stereotypies with a significantly higher score and shorter latency in onset in conditioned than in pseudoconditioned rats. Rats conditioned with the lowest dose showed a significantly longer total duration and a shorter latency in onset of akinesia and ptosis. In rats conditioned with the largest dose (2.0 mg/kg), administration of the lowest dose on the test day produced no stereotypies; neither the akinesia nor the ptosis were different between conditioned and pseudoconditioned rats, but yawning occurred with a higher frequency and a shorter latency in pseudoconditioned rats. When rats were conditioned with the lowest dose and tested with 0.5 mg/kg, the level of stereotypies was identical in both groups of rats, whereas akinesia and ptosis were not observed. Yawning and penile erections occurred more frequently, but for short periods only, in conditioned rats.The results showed that apomorphine-induced stereotypies, akinesia and ptosis could be conditioned, and the conditioned effects mimicked the unconditioned responses, which depended on the dose. Conditioned and unconditioned signs of an increased dopaminergic neurotransmission, observed after large doses of apomorphine, thus acted in a synergistic way; the same applied to conditioned and unconditioned signs observed after a small dose and were perhaps due to a decreased dopaminergic transmission. In contrast, when conditioned and unconditioned signs acted in a mutually antagonistic way (increased vs. decreased dopaminergic transmission), the unconditioned signs predominated. Send offprint requests to K. Kuschinsky at the above address     

One trial conditioning with apomorphine is blocked by cycloheximide

Rats with unilateral 6-hydroxydopamine lesions of substantia nigra were treated with 0.05 mg/kg apomorphine and observation of their circling behavior was made. Twenty minutes after the apomorphine treatment they were injected with saline or 2 mg/kg cycloheximide. Two weeks after drug treatment, control animals exhibited rapid contralateral rotation in response to being placed in the rotation environment. This conditioned rotation was not observed in cycloheximide-treated animals. After the first test trial animals received a second apomorphine administration, this time followed by saline injection in both groups. Subsequent to the second apomorphine treatment both groups showed conditioned rotation.     

Conditioning of behavioural effects produced by an intermediate dose of apomorphine: hypokinesia,ptosis and stereotypies

Summary Apomorphine, in an intermediate dose (0.18 mg/ kg s.c.) decreased dopamine turnover and produced signs generally attributed to a decrease in dopaminergic neurotransmission, e.g. ptosis and yawning, as well as signs of an increased stimulation of dopamine receptors in dopaminoceptive target neurones, e.g. stereotyped sniffing. In contrast, the former signs were exclusively observed after smaller doses and the latter after larger doses of apomorphine. Since it had been shown in previous studies that these signs, except yawning, could be conditioned in association with discriminative stimuli in the environment, the present study using conditioning experiments with this intermediate dose aimed at determining, 1. the time course of each conditioned response, 2. the interaction of conditioned and unconditioned responses, and 3. the conditions under which hypokinesia occurred. In each series, conditioned animals were compared with pseudoconditioned controls. Rats were conditioned for 8 days with apomorphine, and on day 9, treated with saline in presence of the conditional stimuli (a test cage in combination with acoustic and olfactory stimuli). In contrast to pseudoconditioned controls, ptosis and stereotyped behaviour were observed in conditioned rats, sometimes occurring alternatingly. These signs closely resembled the direct, unconditioned pharmacological effects. In addition, akinesia occurred after conditioning, although it was never manifest as a pure drug response, nor during the conditioning period. In contrast, yawning was observed in pseudoconditioned as well as in conditioned rats, although slightly more frequently in the former animals. Subsequently, the rats were again conditioned (or pseudoconditioned) on days 10–14 with apomorphine and both groups tested with the same dose (0.18 mg/kg) of apomorphine in the presence of the conditional stimuli. Both ptosis and stereotypies were significantly enhanced in conditioned animals, indicating synergistic interactions between conditioned and direct, pharmacological behavioural effects. In all cases the conditioned effects lasted for about 30 min.The results show that, after conditioning with an intermediate dose of apomorphine, both signs typical of a low dose of apomorphine and those characteristic of a large dose can be conditioned and sometimes occur alternately. Send offprint requests to K. Kuschinsky     

On the possible involvement of glutamate receptors in conditioning of behavioural effects of apomorphine

It was shown previously that behavioural effects of apomorphine (locomotor activation and stereotyped behaviour) can be conditioned when they are associated with well-defined environmental stimuli. In the present study, the hypothesis was tested that glutamatergic mechanisms play an important role either in formation of conditioned responses to apomorphine or in the expression of previously established conditioned responses. For this purpose, two blockers of glutamate receptors were applied, either MK-801 (dizocilpine), a non-competitive, but selective blocker of NMDA-type receptors or MLV-6976, a non-selective blocker of glutamate receptors. MK-801 produced some locomotor activation by itself in a dose-dependent way (0.125–0.50 mg/kg ip). The locomotor activation produced by 0.25 mg/kg could not be conditioned. When rats were conditioned 9 times with 2 mg/kg apomorphine after pretreatment with 0,25 mg/kg of MK-801, this pretreatment did not prevent the development of apomorphine-conditioned locomotor activity or stereotypies which appeared when the rats were treated with saline in presence of the conditioned stimuli. Similar results were obtained when rats were conditioned 7 times with the same dose of apomorphine after pretreatment with 20 mg/kg ip MLV-6976, which drug did not induce any visible alterations in motility by itself. When rats were conditioned 7 times with 2 mg/kg apomorphine alone and tested with MK-801 (0.25 mg/kg) in the presence of the conditioned stimuli, neither locomotor activity nor stereotypies appeared as conditioned responses. When rats were conditioned with the same dose of apomorphine alone and tested with MLV-6976 (20 mg/kg ip), stereotypies did not appear as conditioned responses, but some locomotor activity occurred. The results suggest that glutamatergic mechanisms are not relevant for the development of conditioned responses to apomorphine, but might be of some relevance for the expression of previously established conditioned responses.     

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     

Direct dopamine agonist-like activity conditioned to cocaine

Rats were lesioned unilaterally by infusions of 6-hydroxydopamine aimed at substantia nigra. In subsequent behavioral testing, apomorphine treatment resulted in rotation (circling) directed contralaterally with respect to the lesion and cocaine treatment induced ipsilaterally directed rotation. When 0.05 mg/kg apomorphine and 10 mg/kg cocaine were administered simultaneously, rotation appropriate for apomorphine resulted. After a number of paired administrations, treatment with cocaine alone resulted in apomorphine-like rotation.     

A conditioned anti-parkinsonian drug effect in the hemi-parkinsonian rat

In two separate experiments contralateral rotation was classically conditioned in hemi-Parkinsonian rats. In the first experiment, ten rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, which produced ipsiversive circling, were given five daily injections of the dopamine receptor agonist apomorphine (0.5 mg/kg) to induce circling contralateral to the lesion hemisphere. One half of the rats (the conditioning group) were placed in a novel environment for 15 min during each apomorphine treatment. Subsequently, when placed into this environment 3, 10, 17, and 24 days after the final apomorphine injection, the conditioning group spontaneously rotated contalateral to the lesion hemisphere, whereas a similarly drug-treated non-conditioned group spontaneously rotated ipsilateral to the lesion hemisphere. On day 26, all rats were given a 2.0 mg/kg injection of d-amphetamine, which generated ipsilateral rotation in all rats in their home environment, but when placed in the conditioning environment, the conditioned group rotated contralateral whereas the non-conditioned group rotated ipsilateral. In the second experiment, eight rats with unilateral destruction of dopamine neurons were given differential conditioning in two novel environments. In every case, environments associated with 0.5 mg/kg apomorphine treatment induced contralateral rotation when the rats were tested without drug but ipsilateral rotation in environments not associated with apomorphine. These findings suggest a role for respondent or Pavlovian conditioning in the pharmacological management of Parkinsonism. Offprint requests to: R. Carey     

Apomorphine-induced pecking in pigeons classically conditioned to environmental cues

The dopamine agonist apomorphine elicits protracted pecking when injected systemically (1 mg/kg) into pigeons. In two experiments it was investigated whether apomorphine would function as an unconditioned stimulus in the classical conditioning of pecking in these animals. An experimental design based on a differentiation procedure was used so that possible pseudoconditioning effects were controlled. Two differently coloured test chambers served as negative (CS-) and positive conditioned (CS+) stimuli. During the training phase the subjects experienced the former while injected with saline, and the latter while injected with apomorphine. In later tests not involving any injections the pigeons made significantly more pecks (conditioned response) in the CS+ chamber than in the CS-chamber. In the first and second experiments the conditioned stimuli were, respectively, discrete and diffuse visual cues, but both had similar effects. The conditioning obtained may explain sensitization effects that are observed with repeated apomorphine injections. Apomorphine probably also functions as a positive reinforcer for instrumental conditioning in pigeons.     

Apomorphine conditioning and sensitization: The paired/unpaired treatment order as a new major determinant of drug conditioned and sensitization effects

Repeated treatments with psychostimulant drugs generate behavioral sensitization. In the present study we employed a paired/unpaired protocol to assess the effects of repeated apomorphine (2.0 mg/kg) treatments upon locomotion behavior. In the first experiment we assessed the effects of conditioning upon apomorphine sensitization. Neither the extinction of the conditioned response nor a counter-conditioning procedure in which we paired an inhibitory treatment (apomorphine 0.05 mg/kg) with the previously established conditioned stimulus modified the sensitization response. In the second experiment, we administered the paired/unpaired protocol in two phases. In the second phase, we reversed the paired/unpaired protocol. Following the first phase, the paired group alone exhibited conditioned locomotion in the vehicle test and a sensitization response. In the second phase, the initial unpaired group which received 5 paired apomorphine trials during the reversal phase did not develop a conditioned response but developed a potentiated sensitization response. This disassociation of the conditioned response from the sensitization response is attributed to an apomorphine anti-habituation effect that can generate a false positive Pavlovian conditioned response effect. The potentiated sensitization response induced by the treatment reversal protocol points to an important role for the sequential experience of the paired/unpaired protocol in behavioral sensitization.     

Suppression of play fighting by amphetamine: effects of catecholamine antagonists, agonists and synthesis inhibitors

Moderate doses of amphetamine and methylphenidate profoundly depress play fighting in juvenile rats. To test the idea that this behavioral effect was dependent on the release of catecholamines (CAs) we administered haloperidol (0.05-0.8 mg/kg), chlorpromazine (0.5-5 mg/kg), phenoxybenzamine (0.5-20 mg/kg) or propranolol (0.5-20 mg/kg) alone or in combination with 0.5 or 1 mg/kg d-amphetamine sulfate. None of these CA antagonists reversed the suppression of play fighting (indexed by pinning) caused by amphetamine, but at higher doses haloperidol, chlorpromazine and phenoxybenzamine depressed both pinning and rearing. The presynaptic NE agonist clonidine (0.05-0.2 mg/kg) also failed to block the effects of amphetamine on play; instead it too depressed both pinning and rearing. Finally the CA synthesis inhibitor, alpha-methyltyrosine (total dose: 100 mg/kg) did not attenuate the suppression of play by amphetamine. Ephedrine (10-80 mg/kg) mimicked the effects of amphetamine on pinning, but apomorphine did not. At doses from 0.125-0.5 mg/kg apomorphine stimulated pinning while 1 mg/kg had no effect. The present findings confirm earlier reports that amphetamine suppresses play fighting but the mechanism of action remains obscure.     

Effects of morphine and LSD on the classically conditioned nictitating membrane response

Two experiments were carried out to determine the effects of LSD and morphine on the unconditioned nictitating membrane response of the rabbit elicited by 5 intensities of a 100 msec puff of air directed at the cornea, and on the acquisition of conditioned responses to a tone and light conditioned stimulus using the air-puff as an unconditioned stimulus. In Experiment 1, LSD tartrate (0.013 mg/kg) had no effect of the frequency, amplitude, magnitude or latency of the unconditioned response. However, LSD significantly enhanced the rate of acquisition of conditioned responses to both tone and light conditioned stimuli. In Experiment 2, morphine sulfate (5 mg/kg) had no effect on the frequency, amplitude, magnitude or latency of the unconditioned response, but significantly retarded the acquisition of conditioned responses to both tone and light conditioned stimuli. The results indicated that the enhancement of acquisition produced by LSD and the retardation of acquisition produced by morphine were not due to effects of the drugs on either the sensory processing of the air-puff unconditioned stimulus or on the motoric expression of the unconditioned response.     

Expression of cocaine-induced conditioned place preference in apomorphine susceptible and unsusceptible rats

Differences in cocaine self-administration can be attributed to differences in the rewarding value that cocaine has for the individual. An ongoing debate, however, exists whether a high rewarding or a low rewarding value leads to an increase in self-administration. To investigate which of these two alternatives is correct, we investigated the occurrence of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats. We have recently shown that under specific environmental conditions (challenged-not habituated to the environment-as measured by distance travelled) apomorphine susceptible rats consistently self-administer more cocaine than apomorphine unsusceptible rats do. As conditioned place preference allows the assessment of the rewarding value of cocaine, we investigated the expression of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats under the same conditions as the self-administration experiments in order to establish whether the rewarding value of cocaine is greater or smaller in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats. The data clearly showed that challenged apomorphine susceptible rats had a preference for the cocaine-paired compartment with lower doses of cocaine (10 mg/kg) than challenged apomorphine unsusceptible rats. Apomorphine unsusceptible rats expressed conditioned place preference only with the highest dose tested (20 mg/kg). On the basis of these data, we concluded that the rewarding value that cocaine has in challenged apomorphine susceptible rats is greater than that in challenged apomorphine unsusceptible rats. It is suggested that challenged apomorphine susceptible rats self-administer more of a lower dose of cocaine than challenged apomorphine unsusceptible rats do, because the rewarding value of cocaine is greater in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats.     

Sensory and associative effects of morphine and naloxone in classical conditioning of the rabbit nictitating membrane response

In Experiment I, classical conditioning of the rabbit's nictitating membrane response was accomplished by the pairing of tone and light conditioned stimuli with a shock unconditioned stimulus applied to the paraorbital region of the head. Morphine (5 mg/kg) significantly retarded the acquisition of conditioned responses to both conditioned stimuli. Moreover, morphine had no effect on nonassociative responding (baseline responding or responding to tone and light stimuli) or on the latency and amplitude of the unconditioned response elicited by shock during the explicitly unpaired presentations of tone, light and shock stimuli. The retardant effect of morphine on acquisition of conditioned responses was blocked by naloxone (1 mg/kg). In Experiment II, morphine (0.2–10 mg/kg) had no effect on the intensity threshold of the shock unconditioned stimulus for elicitation of unconditioned responses or on the latencies of the elicited responses. However, morphine (5 and 10 mg/kg) did produce a small but significant decrease in the amplitude of unconditioned responses elicited by the two highest shock intensities employed (3 and 4 mA). This latter effect of morphine was completely blocked by naloxone (1 mg/kg). In Experiment III, morphine (5 mg/kg) blocked the sensory processing of a tone conditioned stimulus, in previously trained animals, as measured by a significant (24 dB) elevation in the intensity threshold of the conditioned stimulus for elicitation of conditioned responses and an increase in the latency of the elicited response. Naloxone (1 mg/kg) completely blocked the effects of morphine on the sensory processing of the tone-conditioned stimulus. The retardant effect of morphine on the acquisition of conditioned responses appears to be primarily due to an action on opioid receptors that produces a decrease in the sensory processing of the conditioned stimulus.     

Pharmacologically specific pretreatment effects on apomorphine-mediated conditioned taste aversions in rats

Pretreatment with pimozide (0.2-1.2 mg/kg) reduced a conditioned taste aversion produced by apomorphine (0.4 mg/kg) in a dose-related manner. This pretreatment effect was pharmacologically specific as shown by the inability of pimozide to prevent a conditioned taste aversion produced by nicotine (0.4 mg/kg). The results argue against the hypothesis that "proximal pre-exposure" effects are always non-specific and indicate that further pharmacological characterisation of drug-induced conditioned taste aversion may be possible. Pretreatment with a peripherally-acting antiemetic compound, domperidone, did not prevent apomorphine producing conditioned taste aversions. These data suggest that conditioned taste aversions produced by apomorphine are mediated through central dopamine receptors unrelated to the emetic properties of apomorphine and are not a result of conditioned nausea.     

Expression of morphine-conditioned hyperactivity is attenuated by naloxone and pimozide

The present experiments assessed whether morphine-conditioned hyperactivity could be attenuated by either the opiate antagonist naloxone or the dopamine antagonist pimozide. Both of these antagonists were shown to block the unconditioned hyperactivity induced by 2 mg/kg morphine (Experiment 1). Rats were then conditioned by pairing this dose of morphine repeatedly with a distinctive environment (Experiment 2). Following several drug-environment pairings, rats displayed a hyperactive conditioned response (CR) when exposed to the environment in the absence of the drug. CR expression was counteracted by 1 mg/kg naloxone and was attenuated by pimozide (0.25, 0.33, and 0.4 mg/kg) in a dose-related manner. These findings suggest that the unconditioned and conditioned hyperactive responses produced by morphine may involve similar neuropharmacologic substrates.     

Subcutaneous injections of apomorphine, stimulus generalization and conditioning: serious pitfalls for the examiner using apomorphine as a tool.

This report shows that stimulus generalization occurs in rats conditioned by a single injection of apomorphine. The data suggest that apomorphine initially acts as an unconditioned stimulus (UCS) of an unconditioned response (UCR) that, in turn, produces stimuli which become conditioned stimuli (CS) of a conditioned response (CR) having a nature identical to that of the UCR. The study also shows that behaviour elicited by a subcutaneous injection of apomorphine depends on the part of the body selected for administration. The mentioned properties should be taken into account when apomorphine is used as a tool in studies on brain and behaviour.     

Reinstatement by caffeine of an extinguished conditioned dopaminergic drug response

An experimental study of extinction of conditioned drug-induced effects was carried out to determine: 1) duration of the extinction effect; and 2) stability of extinction as determined by a challenge with a stimulant drug. Twelve animals with unilateral 6-hydroxydopamine (6-OHDA) substantia nigra lesions were assigned to paired and unpaired treatment groups (n = 6) in a Pavlovian conditioning paradigm. The paired animals received apomorphine (0.05 mg/kg SC) immediately prior to placement into a test chamber and the unpaired animals received the apomorphine 30 min following test chamber placement. The two groups were matched for apomorphine-induced contralateral rotation prior to the conditioning treatment. Following Pavlovian conditioning, the paired group, but not the unpaired group, exhibited contralateral rotation in a nondrug test trial. This conditioned response underwent extinction after one nondrug extinction trial and the extinction effect persisted for 2 months. When tested with caffeine (10 mg/kg), the paired animals again exhibited substantial contralateral rotation. In contrast, the unpaired animals showed only an increase in ipsilateral rotation in response to the caffeine treatment. The drastically different response to caffeine in the paired and unpaired animals was not due to prior apomorphine exposure per se or due to 6-OHDA lesion-induced differences in striatal dopamine depletion. Rather, the effect of caffeine on rotation behavior was determined by the Pavlovian drug conditioning procedures carried out several months earlier prior to caffeine testing.     

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'.     

Conditioning of pre- and post-synaptic behavioural responses to the dopamine receptor agonist apomorphine in rats

We investigated whether pharmacological effects of the dopamine agonist apomorphine can be conditioned by establishing an association of apomorphine administration with exteroceptive cues. Apomorphine was repeatedly administered and subsequently, the rat was put into a test cage and exposed to an acoustic and an olfactory stimulus (conditioned rats). Control animals (pseudoconditioned rats) were treated with the same pharmacological schedule of apomorphine not temporally associated with the stimuli. On the test day, both groups were injected with saline and exposed to the stimuli described.The stereotyped behaviour produced by large doses of apomorphine (0.5 or 2.0 mg/kg SC), namely sniffing, licking and gnawing, could be conditioned in a pronounced way. During the conditioning period, a change in the stereotypies was observed with regard to the time-course (earlier occurrence) and to the character of the stereotypies (from sniffing to licking and gnawing), when 0.5 mg/kg apomorphine was used, but not with the dose of 2.0 mg/kg. The conditioned responses showed a relatively uniform distribution during the observation period with some increase towards the end of the observation period. Some signs produced by a low dose of apomorphine (0.07 mg/kg SC), namely hypomotility and ptosis, but not yawning, could also be conditioned, although in a less pronounced way. An intermediate dose of apomorphine (0.18 mg/kg SC) produced both signs observed after large doses and those observed after a small dose, occurring alternatingly. Both types of signs could be conditioned using this dosage. Conditioning did not alter striatal or mesolimbic dopamine turnover.These results suggest that only behavioural signs due to an activation of postsynaptic dopamine receptors, but also some symptoms produced by an activation of dopamine autoreceptors can be conditioned.