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     

Conditioning of behavioural signs produced by nomifensine and by B-HT 920 in rats

Conditioning of behavioural effects produced by two drugs acting differently upon dopaminergic neurotransmission was studied. Nomifensine and the putative dopamine autoreceptor agonist B-HT 920 produce contrasting effects on motility, namely increases in locomotor activity and stereotypies as compared to hypokinesia and ptosis. The administration of each of these drugs (US) was repeatedly associated with well-defined environmental stimuli (CS): a wire cage associated with an auditory and on olfactory stimulus. The rats were conditioned for 7 days with 20 mg/kg nomifensine IP each day. After conditioning, the rats were treated with the solvent alone in presence of the CS. Not only did sniffing and licking occur, but also gnawing, even though the latter response was not evident after acute administration of the drug or during the conditioning period. Nomifensine (20 mg/kg IP) also acutely decreased the ratio of 3,4-dihydroxyphenylacetic acid/dopamine concentrations (DOPAC/DOPAMINE); this ratio was not altered in the conditioned rats, 60 min after solvent administration in presence of the CS. Rats were conditioned with 0.02 mg/kg IP B-HT 920 daily for 8 days. During the conditioning phase, akinesia and ptosis showed a slight enhancement and a faster onset. After conditioning, when the rats were treated with the solvent alone, the majority of them showed akinesia and/or ptosis during the observation period, in contrast to pseudoconditioned controls. When these rats were conditioned or pseudoconditioned, respectively, with B-HT 920 for further 5 days using 0.02 mg/kg again, treatment with the same dose in presence of the CS produced a significant enhancement and acceleration of these signs in conditioned as compared with pseudoconditioned control rats. The results show that stereotypies producd by nomifensine and akinesia and ptosis produced by B-HT 920 can be conditioned and that, in addition, a sign of stereotypies which was not manifest during the conditioning period appeared as conditioned response.     

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     

Conditioned tolerance to haloperidol- and droperidol-induced catalepsy

Summary The possible mechanisms of conditioned tolerance to the cataleptogenic effects of haloperidol and droperidol were studied in order to discriminate between classical and conditioned tolerance. Rats were conditioned by repeated administration (19–27 times) of haloperidol (1.5 mg/kg i. p.) or droperidol (1.5 mg/kg i. p.), respectively, in the presence of a sum of defined environmental (auditory, olfactory and tactile) stimuli. The animals were compared with pseudoconditioned rats, which underwent the same number of drug injections and exposures to the environmental stimuli, but neither were associated. In part of the experiments, one further group of rats was repeatedly treated with only solvent in the presence of the environmental stimuli. Rats conditioned with haloperidol or droperidol showed tolerance to the cataleptogenic effect of a test dose of haloperidol (1.5 mg/kg i. p.) or droperidol (1.5 mg/kg i.p.), respectively, when they were tested in presence of the defined conditioning stimuli. The rats conditioned with droperidol showed significantly less catalepsy than the pseudoconditioned animals 30 min after droperidol administration, whereas in rats conditioned with haloperidol, the catalepsy was less pronounced no sooner than 120 min after haloperidol administration. This was a manifestation of conditioned tolerance. In rats pseudoconditioned with droperidol, the catalepsy was similar to that produced by the drug in drug-naive rats, suggesting no classical tolerance due to repeated administration of the neuroleptic drug. The dopamine turnover in striatum or nucleus accumbens after administration of 1.5 mg/kg of haloperidol i.p. was not altered in rats conditioned with haloperidol when compared with pseudoconditioned animals. The stereotypies produced by apomorphine (0.16 mg/kg s. c.) were most pronounced in conditioned, less pronounced in pseudoconditioned and very small in drug-naive rats. These result suggest that the conditioned tolerance to the neuroleptic drugs is connected with an increased sensitivity of the basal ganglia to dopaminergic drugs. In another series of experiments, rats were conditioned with apomorphine 8 times and tested with 0.66 mg/kg of droperidol i.p. Rather unexpectedly, the catalepsy was significantly more pronounced in conditioned than in pseudoconditioned animals. This observation suggests that the type of conditioned effect, which becomes manifest, depends in part on the drug used in the presence of the conditioned stimuli.Send offprint requests to K. Kuschinsky     

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.     

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.     

Conditioning of nicotine effects on motility and behaviour in rats

Summary Nicotine produces behavioural signs which are, in part, characteristic of dopaminergic activation. In the present study, it was investigated, to which degree these signs can be conditioned. The drug produced dose-dependent (0.15–0.60 mg/kg s.c.) increases in locomotor activity, hyperkinesia and stereotyped sniffing. The effects produced by 0.6 mg/kg nicotine were significantly inhibited by mecamylamine (1 mg/kg i. p.), but only in part by haloperidol (0.2 mg/kg i. p.). In a subsequent series, the administration of nicotine (0.6 mg/kg s.c.) was repeatedly associated with well-defined environmental (conditioned) stimuli: a wire cage associated with an auditory and an olfactory stimulus. Another group was pseudoconditioned, a third group remained drug-naive. When the animals were given saline in presence of the conditioned stimuli 24 h after the last conditioning session, locomotor activity, hyperkinesia and stereotyped sniffing were significantly higher in conditioned than in pseudoconditioned and drug-naive rats. Similarly, when the rats were injected with nicotine (0.6 mg/kg s. c.) in presence of the conditioned stimuli 24 h after the last conditioning session, locomotor activity and stereotyped sniffing were most pronounced in the conditioned animals. These results demonstrated that behavioural effects of nicotine can be conditioned. Phenomena of this kind might contribute to the addictive behaviour to nicotine. Send offprint requests to K. Kuschinsky at the above address     

Conditioning of apomorphine effects: simultaneous analysis of the alterations in cortical electroencephalogram and behaviour

Summary The possible conditioning of pharmacological effects of apomorphine on the electroencephalogram was studied using telemetric recordings in rats. Previous studies have shown that apomorphine-induced stereotyped behaviour can be conditioned: after repeated pairings of defined stimuli with the drug effect, the presentation of the external stimuli alone elicited stereotype sniffing, licking, and gnawing. Since apomorphine, an agonist at dopamine receptors, also produces a characteristic EEG pattern with an increase of power in the alpha-1 band, the possibility that this effect could also be conditioned was studied.In fact, conditioning with a dose of 0.5 mg/kg apomorphine (s. c.) led to a significant increase in the number of short-lasting episodes with enhancement of the power in the alpha-1 range in the presence of the conditioned stimuli, according to a comparison of the results obtained in the conditioned group and those of the controls (pseudoconditioned).Moreover, behavioural studies were performed simultaneously in order to find possible correlations between conditioned effects on EEG and conditioned alterations in behaviour. In general, a fair correlation between the increase of power in the alpha-1 band and stereotyped behaviour was found. This was also the case during extinction, when the conditioned stimuli were repeatedly uncoupled from apomorphine administration: both behavioural parameters and EEG alterations showed similar time-courses and had almost disappeared during the fourth extinction session. Send offprint requests to: K. Kuschinsky at the above address     

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.     

Effects of apomorphine and haloperidol on “spontaneous” stereotyped licking behaviour in the Cebus monkey

Three recently arrived drug naive Cebus apella monkeys with spontaneous stereotyped oral movements were treated with apomorphine and haloperidol using a wide dose range. Low doses of apomorphine (0.05–0.1 mg/kg) suppressed the oral stereotypies without affecting normal behaviour such as grooming and scratching. Higher doses of apomorphine (0.25–1.0 mg/kg) and haloperidol (0.01–0.1 mg/kg) also decreased or abolished the oral stereotypies, but induced generalized stereotypies (apomorphine) or dystonia/parkinsonism (haloperidol), suppressing normal behaviour. The findings indicate that dopamine is involved in these presumably stress-induced (not drug-induced) stereotypies.     

Alterations in regional energy metabolism in rat brain produced by small and by large doses of apomorphine: possible relations to autoreceptors

Dose-dependent changes in behavioural patterns and in local cerebral glucose utilization (LCGU) following subcutaneous application of apomorphine were measured in conscious, unrestrained rats by means of a scoring system and of the autoradiographic [C14]2-deoxyglucose technique, respectively. The behavioural patterns of akinesia, ptosis, yawning and penile erections were scored. Akinesia and ptosis were most prominent after 0.02 and 0.07 mg/kg apomorphine but not after 0.18 mg/kg. Maximal scores for yawning and penile erections were obtained after 0.07 mg/kg. LCGU was not significantly changed after 0.07 mg/kg except for decreases in the cingulate cortex and hypothalamus. Apomorphine 0.5 mg/kg decreased LCGU in the cingulate, parietal and occipital cortex, anteromedial and lateral thalamus and lateral habenula but increased it in laminae IV and VI of the sensorimotor cortex, in the parafascicular nucleus of the thalamus, and in some parts of the basal ganglia and related nuclei. Similar changes in LCGU occurred after 2.0 mg/kg apomorphine, which also increased LCGU in the ventral tegmental area. The lower dose did not produce changes in LCGU opposite to those occurring after larger doses. The data obtained with LCGU do not support the idea that behavioural effects after low doses of apomorphine are elicited by activation of dopamine autoreceptors.     

Conditioned effects of apomorphine are manifest in regional EEG of rats both in hippocampus and in striatum

Summary Previously, in own studies, it was shown that stereotyped behaviour produced by apomorphine can be conditioned if the drug is repeatedly paired with defined environmental stimuli (conditioned stimuli, CS). Eventually, the presentation of CS alone produces stereotyped behaviour as conditioned response (CR). Furthermore, in electrocorticographic recordings it could be demonstrated that the characteristic pattern following acute apomorphine treatment, namely a selective increase in the power of the alpha-1 band, could be conditioned as well.In the present study, regional EEG was recorded in the striatum and in the hippocampus of freely moving rats. For conditioning, apomorphine (0.5 mg/kg s.c.) was paired with auditory and olfactory stimuli as CS for seven times, and on the eighth day the drug was substituted by the solvent in the presence of the CS. The effects were compared with those obtained in pseudoconditioned controls.Acute apomorphine administration led to an increase in power in the alpha-1 band (7.00–9.50 Hz), which effect was obvious in the hippocampus, above the cortex and in the striatum. After performing the conditioning procedure, these effects in regional EEG were found to be conditioned as well: as CR, activation in power in the alpha-1 band in hippocampus and striatum were manifest in the presence of the CS, but in absence of the drug. These effects occurred sporadically, but with a significantly higher frequency than in the pseudoconditioned controls.The results suggest that both the hippocampus and the striatum play important roles in classical conditioning of apomorphine effects which are primarily mediated by the striatum. Correspondence to K. Kuschinsky at the above address     

Alpha-methyltyrosine blocks the expression of rotation classically conditioned with apomorphine.

Rats with unilateral 6-hydroxydopamine lesions of substantia nigra rotate (circle) when placed, undrugged, in the environment in which they have previously been treated with apomorphine. This conditioned rotation, like the unconditioned rotation which acutely follows the administration of apomorphine, is directed away from the side with the lesion, i.e., the rotation is contralateral. Here, rats that had been administered apomorphine weeks earlier were tested, in a crossover design, for the expression of conditioned rotation following treatment with saline and with alpha-methyltyrosine. When administered four hours prior to testing, 100 mg/kg alpha-methyltyrosine significantly antagonized the expression of classically conditioned rotation. In a second group of animals, alpha-methyltyrosine had no effect on the unconditioned rotation induced by 0.05 mg/kg apomorphine.     

Psychopharmacological effects of nomifensine enantiomers

The effects of enantiomers of nomifensine were compared in five psychopharmacological tests in which (+/-)-nomifensine is active. In mice, (+)-nomifensine increased motor activity at 16 mg/kg, 8 mg/kg reduced the hypothermia and ptosis induced by reserpine and antagonized the hypothermia induced by 16 mg/kg of apomorphine. (+)-Nomifensine 4 mg/kg potentiated yohimbine toxicity. (-)-Nomifensine 4,8, or 16 mg/kg was inactive in all these tests. In rats, (+)-nomifensine 8 mg/kg induced stereotyped movements whereas (-)-nomifensine 64 mg/kg did not produce stereotypies.     

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.     

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.     

Effect of conditioning with d-amphetamine on the extracellular concentration of dopamine and its metabolites in the striatum of behaving rats

The effect of classical conditioning with d-amphetamine on the extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of awake, freely moving rats was studied using microdialysis. This was done in order to test, whether there occurred alterations in DA release as conditioned responses in the striatum. The first series of experiments studied the acute effects of d-amphetamine on the concentration of DA and its metabolites DOPAC and HVA. d-Amphetamine (2 mg/kg, s.c.) increased extracellular DA and decreased DOPAC and HVA. Behaviorally, it led to stereotyped locomotor activation and sniffing. In principle, these observations confirmed earlier findings. In a second series, conditioned responses to d-amphetamine were studied. Rats were implanted with guide cannulas prior conditioning experiments started. For conditioning experiments, the rats were divided into three groups: conditioned group, pseudoconditioned group and a drug-naive control group. After 7 daily training sessions with d-amphetamine (2 mg/kg), on the 8th day, the test day, rats were injected with saline and exposed to the conditional stimuli, while they were observed for their stereotyped, conditioned response. Additionally, microdialysis was performed in order to observe possible changes in the extracellular transmitter or metabolite concentrations. Conditioning with amphetamine led to conditioned stereotypic behavior. In comparison with the pseudoconditioned rats, there was an increase in DA release as conditioned response to amphetamine. In pseudoconditioned rats. DOPAC and HVA were slightly higher than in both other groups. DOPAC and HVA were lower in rats conditioned to d-amphetamine when compared with the pseudoconditioned ones. The results suggest that with regard to DA release, the conditioned responses to d-amphetamine mimicked the acute pharmacological responses. The same is valid for the DA metabolites, although in the opposite direction — they mimicked decreases. Furthermore, the conditioned DA responses to d-amphetamine might contribute to conditioned behavioral responses observed in these experiments. Correspondence to: K. Kuschinsky at the above address     

A comparison of different sensory stimuli in producing conditioned apomorphine effects

In previous studies, it was shown that apomorphine-induced stereotyped behaviour could be conditioned when apomorphine was repeatedly paired with sensory stimuli (CS). Since in these experiments, the sum of various sensory stimuli were applied, it seemed of interest to use each sensory stimulus separately in order to evaluate the relevance of each of the stimuli for the development of the conditioned responses (CRs). Therefore, apomorphine (0.5mg/kg s.c.) was repeatedly (six times) paired either with an auditory, an olfactory, a tactile or a compound (auditory + olfactory + tactile) stimulus. On the seventh (drug-free test) day, the rats were injected with solvent in the presence of the CS previously applied. It was shown that the olfactory stimulus alone when used as CS produced similar CRs (in particular, stereotyped sniffing and licking) as the compound stimulus, whereas the other stimuli applied did not noticeably contribute to the development of the CRs. Furthermore, similarly to the compound stimulus, the olfactory stimulus, but not the auditory or tactile one, enhanced the apomorphine-induced stereotypies in the presence of the CS. This result suggests that the application of olfactory stimuli might be of particular relevance for the development of conditioned dopaminergic responses.     

Reinstatement of cocaine-reinforced responding in the rat

Non-contingent priming drug injections and conditioned stimuli associated with drug injections led to reinstatement of responding after a period of extinction. Rats implanted with intravenous catheters were trained to self-administer cocaine (1 mg/kg/injection), and then given daily test sessions consisting of a period of self-administration followed by extinction conditions. Test drug injections or conditioned stimuli were presented during extinction and the latency to the first response and the total number of responses following the treatment were measured. Cocaine injections of 0.5, 1.0, and 2.0 mg/kg restored responding during extinction, regardless of the duration of the extinction period (between 10 min and 180 min) since drug self-administration. Amphetamine, apomorphine, and morphine but not ethanol, heroin, or methohexital reinstated previously cocaine-reinforced responding. Amphetamine, cocaine, and morphine did not increase responding in animals trained to bar press only for food reinforcement, suggesting that the reinstatement effect is specific to drug-reinforced responses. The final experiment showed that a tone that had been paired with drug infusions acquired a statistically significant tendency to facilitate responding when tested during extinction but this effect disappeared after the first test presentation of the tone.     

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.