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     

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     

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     

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.     

Effects of MDA on classical conditioning of the rabbit nictitating membrane response

In Experiment 1, classical conditioning of the rabbit's nictitating membrane response (NMR) was accomplished by pairing tone and light conditioned stimuli (CSs) with a shock unconditioned stimulus (UCS). MDA impaired the acquisition of conditioned responses (CR) to a tone-CS, while significantly enhancing CR acquisition to a light-CS. Experiment 2, employing explicitly unpaired CS, UCS training, revealed no reliable effects of MDA upon nonassociative processes. Subsequent efforts determined if MDA's CR acquisition effects resulted from alterations in sensory processing of the CS, UCS, and/or UCR motor functioning. Specifically, it was determined that MDA: (a) increased the tone-CS intensity threshold for eliciting CRs (Experiment 3); (b) attenuated the tone-induced reflex modification of the unconditioned NMR (Experiment 4); and (c) enhanced UCR frequency at varying UCS intensities (Experiment 5). It was concluded that MDA's effect upon CR acquisition reflected the drug's effect upon CS and UCS/UCR processing and thereby altered the ability of these components of conditioning to enter into associative learning.     

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.     

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 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.     

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 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     

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.     

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     

The effects of drugs on conditioning and habituation to arousal stimuli in animals

Summary The effects of a number of drugs on conditioned and unconditioned arousal responses (behavioural and electroencephalographic) produced by auditory stimuli in cats are reported. Positive conditioning was achieved by pairing certain auditory stimuli with a painful stimulus (electric shock).Chlorpromazine increased thresholds for both conditioned and unconditioned stimuli and eventually blocked arousal responses completely. Reserpine, which had a delayed effect, caused only a slight rise in the conditioned response but blocked the unconditioned response although this latter effect may have been in part due to habituation.Amphetamine caused a fall in the threshold for unconditioned arousal responses but did not change that for conditioned responses. However, these thresholds could no longer be assessed when doses which produced full alerting were used.LSD 25 also caused a fall in the threshold for arousal to unconditioned stimulus and no change in the conditioned response, but it restored the response to a stimulus which had previously been habituated.The results are discussed in relation to the hypothesis for the sites of action of these drugs in the brain which has been expounded previously.This work has been sponsored by the Office of Scientific Research of the Air Research and Development Command, United States Air Force, Contract No. AF 61 (514)-1184.     

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.     

Haloperidol- and apomorphine-induced changes in pup searching behaviour of house mice

Maternal pup searching behaviour of lactating house mice treated with apomorphine, haloperidol or saline was examined on a running board with a central depression as a nest. Pup searching was elicited by artificial ultrasonic stimuli: a female moved out from the nest either towards a 50 kHz tone (key stimulus) which is adequate to activate species specific pup searching behaviour or towards a 20 kHz tone (neutral stimulus), thus showing her preference for one of these stimuli. Under apomorphine (0.00625; 0.0125; 0.025 mg/kg) the females preferred the key stimulus. Nevertheless apomorphine (0.00625–0.025 mg/kg) prolonged response latencies and shortened the duration of pup searching. At the highest dose (0.05 mg/kg), apomorphine induced stereotyped sniffing. Haloperidol (0.025; 0.05; 0.1 mg/kg) had opposite effects to apomorphine: it lowered the threshold for elicitation, shortened response latencies and prolonged the duration of pup searching. Females treated with haloperidol (0.025–0.1 mg/kg) did not prefer the key stimulus. Changes in response elicitation and in the performance of pup searching induced by apomorphine and haloperidol, respectively, were assumed to be due to i) a reduced and an increased responsiveness to external stimuli respectively, ii) an enhanced and a reduced tendency for response switching respectively, and iii) a preference for spontaneous behaviour in apomorphine-treated females, with an increased dependence on exteroceptive stimuli following haloperidol.     

Sodium pentobarbital: sensory and associative effects in classical conditioning of the rabbit nictitating membrane response

Four experiments were conducted to determine the effects of sodium pentobarbital (0, 3, 9, and 15 mg/kg) on the acquisition of the rabbit's classically conditioned nictitating membrane response (NMR) and to determine the locus of the drug's effects on sensory, motor, associative, and nonassociative processes. In experiment 1, classical conditioning of the NMR was accomplished by pairing tone and light conditioned stimuli (CSs) with paraorbital shock as the unconditioned stimulus (US). The experiment revealed that pentobarbital retarded the acquisition of conditioned responses (CRs) to both tone and light CSs. Experiment 2, employing unpaired CS, UCS presentations, indicated small but significant drug effects on NMR base rate and nonassociative NMRs to the CS. Experiment 3 revealed no significant drug effect on the psychophysical functions relating UCS intensity to UCR frequency or amplitude, nor on the UCS intensity threshold for eliciting UCRs. On the other hand, in experiment 4, the drug significantly impaired CR frequency over an extended range of CS intensities and raised CS intensity threshold. It was concluded that pentobarbital's attenuation of CS intensity also operated to impair CR acquisition.     

Conditioned stereotypy: behavioral specification of the UCS and pharmacological investigation of the neural change

Previous work has shown that conditioned stereotypy can be produced by repeated treatments with d-amphetamine or apomorphine. We replicated this phenomenon and found that, as in previous reports, the amplitude of conditioned stereotypy was about one-third that of the unconditioned stereotypy. On the basis of the hypothesis that the UCS in this conditioning situation is a specific stimulation level of dopamine receptors expressed as a peak behavioral effect (UCR), rats were exposed to the experimental boxes for a brief interval during the peak behavioral effect of the drugs. This procedure produced an amplitude of conditioned stereotypy about two-thirds that of unconditioned stereotypy. The issue of the synaptic mechanism mediating conditioned stereotypy was addressed by examining the effect of pimozide on the behavior. A dose of pimozide that completely blocked apomorphine-unconditioned stereotypy also blocked apomorphine-conditioned stereotypy with no sign of motor impairment. d-Amphetamine-conditioned stereotypy was not completely blocked by a dose of pimozide that completely blocked d-amphetamine-unconditioned stereotypy. The implications of these findings for understanding the neural basis of conditioned stereotypy are discussed.     

Effects of LSD-25 on classical trace conditioning

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

Sensory and associative effects of LSD on classical appetitive conditioning of the rabbit jaw movement response

Three experiments were conducted to determine the effects of LSD (30 nmol/kg) in classical appetitive conditioning of the rabbit jaw movement response (JMR). In experiment 1, LSD significantly enhanced the acquisition of conditioned responses (CRs). The performance of control groups receiving unpaired presentations of the conditioned stimulus (CS) and unconditioned stimulus (UCS) demonstrated that LSD's enhancing effect on conditioning could not be attributed to an elevation in baseline responding, sensitization, or pseudoconditioning. Accordingly, experiments 2 and 3 were conducted to determine whether LSD's enhancement of conditioning could have arisen from its altering the sensory processing of either the CS or UCS, or botj. In experiment 2, LSD was found to have no significant effect on the functions relating UCS magnitude to the frequency, amplitude, or number of sinusoidal peaks comprising each unconditioned response (UCR). In contrast, experiment 3 revealed that LSD significantly enhanced the frequency of CRs to an extended range of CS intensities and lowered the CS intensity threshold. It was concluded that the enhancing effect of LSD on the acquisition of CRs is attributable, at least in part, to the drug's enhancement of the sensory processing of the CS.     

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.