Blocking and sensory preconditioning effects in morphine analgesic tolerance: Support for a pavlovian conditioning model of drug tolerance

Two experiments on rats tested predictions of a Pavlovian conditioning model of drug tolerance which holds that tolerance is the result of compensatory conditioned responses, developed to environmental stimuli accompanying the drug administrations, which attenuate the direct effects of the drug. In Experiment I, the acquisition of tolerance-modulating properties by the tone component of a tone-light compound stimulus which accompanied morphine administrations was reduced by prior light-morphine pairings (blocking). In Experiment II, a tone stimulus acquired tolerance-modulating properties through prior pairings with a light stimulus which later accompanied morphine administrations (sensory preconditioning). These findings are uniquely predicted by the Pavlovian conditioning model of drug tolerance and are incompatible with traditional theories which assign no role to environmental stimuli present at the time of drug administration.     

Extinction of morphine analgesic tolerance

It has been suggested that the analgesic effect of morphine becomes attenuated over the course of successive administrations by a conditional, compensatory, hyperalgesic response elicited by the administration procedure, thus accounting (in part) for analgesic tolerance. On the basis of this associative model of tolerance, it would be predicted that established tolerance would be extinguished by placebo sessions. In experiments of apparently similar design (but conducted by different experimenters in different laboratories), data both confirming and refuting this prediction have previously been published. The present experiment, conducted jointly by the experimenters who reported the divergent findings, was designed to determine the reasons for the different results. It was found that placebo sessions do consistently attenuate morphine analgesic tolerance. Such extinction is not limited to the experimenter, drug preparation, rat strain, or apparatus used in the original, successful demonstration of the phenomenon, but rather is also demonstrable under conditions similar to those used in subsequent experiments which failed to demonstrate extinction of tolerance. Results of the present experiment suggest that the failures to demonstrate extinction of tolerance were attributable to insufficient extinction training.     

A role for CS-US contingency in Pavlovian conditioning

Two experiments evaluated the role of conditioned stimulus-unconditioned stimulus (CS-US) contingency in appetitive Pavlovian conditioning in rats. In both experiments, some groups received a positively contingent CS signaling an increased likelihood of the US relative to the absence of the CS. These groups were compared with control treatments in which the likelihood of the US was the same in the presence and absence of the CS. A trial marker served as a trial context. Experiment 1 found contingency sensitivity. There was a reciprocal relationship between responding to the CS and the trial marker. Experiment 2 showed that this result was not stimulus or response specific. These results are consistent with associative explanations and the idea that rats are sensitive to CS-US contingency.     

The role of awareness in Pavlovian conditioning: empirical evidence and theoretical implications

This article reviews research over the past decade concerning the relationship between Pavlovian conditioning and conscious awareness. The review covers autonomic conditioning, conditioning with subliminal stimuli, eyeblink conditioning, conditioning in amnesia, evaluative conditioning, and conditioning under anesthesia. The bulk of the evidence is consistent with the position that awareness is necessary but not sufficient for conditioned performance, although studies suggestive of conditioning without awareness are identified as worthy of further investigation. Many studies have used inadequate measures of awareness, and strategies for increasing validity and sensitivity are discussed. It is concluded that conditioning may depend on the operation of a propositional system associated with consciousness rather than a separate, lower level system.     

Pavlovian inhibitory conditioning and tolerance to pentobarbital-induced hypothermia in rats

In this experiment we investigated inhibitory Pavlovian conditioning in the development of tolerance to pentobarbital-induced hypothermia. During an initial phase, one group of rats (discrimination group) received training in which, on alternate days, one conditional stimulus (CS+) was associated with administration of 30 mg/kg pentobarbital, and a different conditional stimulus (CS-) was associated with administration of physiological saline. During the phase, control groups received either exposure to both CSs but not the drug or to the drug but no CSs or to neither the CSs nor the drug. Subsequently, half the rats in each group received injections of pentobarbital in the presence of one of the CSs and the remaining half in the presence of the other CS. Rats from the discrimination group injected with pentobarbital in the presence of CS+ displayed the most tolerance (i.e., smallest drug effect), whereas rats from the discrimination group injected with pentobarbital in the presence of CS- displayed the least tolerance (i.e., greatest drug effect). The attenuation of tolerance seen in rats of the discrimination group injected in the presence of CS- provides evidence of inhibitory Pavlovian conditioning. Additional evidence of inhibitory conditioning was provided by the fact that CS2 enhanced the hypothermic effects of pentobarbital in the discrimination group, whereas CS1 attenuated these effects. Implications of the results for the nature of inhibitory conditioning are discussed.     

Anterograde amnesia for Pavlovian fear conditioning and the role of one-trial overshadowing: effects of preconditioning exposures to morphine in the rat

Four experiments studied anterograde deficits in Pavlovian fear conditioning following prolonged exposure to the mu-opioid receptor agonist morphine. Injections of morphine produced temporally graded anterograde amnesia characterized by deficits in contextual and conditioned-stimulus (CS) conditioning 1 or 7 days and selective impairment in CS conditioning 21 days after last injection. This anterograde deficit in conditioning did not recover across a retention interval, was absent when rats were tested immediately after conditioning, and required the presence of an auditory CS. These results suggest that anterograde deficits in Pavlovian fear conditioning emerged from differences in susceptibility to 1-trial overshadowing of context by CS.     

Stimulus generalization: some predictions from a model of Pavlovian conditioning.

Three experiments examined predictions generated by incorporating a common-elements account of stimulus generalization within the Rescorla-Wagner model of conditioning. All experiments employed rats in a conditioned suppression situation. Experiments 1 and 2 found that conditioning of a similar stimulus augmented the excitation controlled by a near-asymptotic target stimulus more than did further conditioning of the target itself. Prior discrimination training between the target and the similar stimulus enlarged this effect, compared with prior discrimination between the target and another dissimilar stimulus. Nonreinforced exposure of the similar stimulus prior to its reinforcement also increased the effect. Experiment 3 examined a related prediction for inhibition. After discrimination training, extinction of the previously reinforced stimulus revealed more inhibition to the previously nonreinforced stimulus when those two stimuli were more similar. These outcomes are consistent with deductions from the present model and encourage further testing of its expansion to the case of stimulus generalization.     

Neuroscience of Pavlovian conditioning: a brief review

Current knowledge on the neuronal substrates of Pavlovian conditioning in animals and man is briefly reviewed. First, work on conditioning in aplysia, that has showed amplified pre-synaptic facilitation as the basic mechanism of associative learning, is summarized. Then, two exemplars of associative learning in vertebrates, fear conditioning in rodents and eyelid conditioning in rabbits, are described and research into its neuronal substrates discussed. Research showing the role of the amygdala in fear conditioning and of the cerebellum in eyelid conditioning is reviewed, both at the circuit and cellular plasticity levels. Special attention is given to the parallelism suggested by this research between the neuronal mechanisms of conditioning and the principles of formal learning theory. Finally, recent evidence showing a similar role of the amygdala and of the cerebellum in human Pavlovian conditioning is discussed.     

No support for dual process accounts of human affective learning in simple Pavlovian conditioning

Dual process accounts of affective learning state that the learning of likes and dislikes reflects a learning mechanism that is distinct from the one reflected in expectancy learning, the learning of signal relationships, and has different empirical characteristics. Affective learning, for example, is said not to be affected by: (a) extinction training; (b) occasion setting; (c) cue competition; and (d) awareness of the CS-US contingencies. These predictions were tested in a series of experiments that employed simple Pavlovian conditioning procedures. Neutral visual pictures of geometric shapes, or tactile conditional stimuli (CS) were paired with aversive electrotactile unconditional stimuli (US). Dependent measures were physiological (skin conductance, blink startle modulation) or verbal (US expectancy, on-line and off-line ratings of CS pleasantness). Different combinations of these dependent measures were employed across different experiments in an attempt to assess affective and expectancy learning simultaneously. Changes in CS pleasantness as indexed by ratings or blink startle modulation were readily observed. However, contrary to the predictions from dual-process accounts, results indicated that acquired CS unpleasantness is subject to extinction, occasion setting, cue competition, and not found in absence of CS-US contingency awareness.     

The incubation theory of fear/anxiety: experimental investigation in a human laboratory model of Pavlovian conditioning

The aim of this work was to test Eysenck's incubation theory of fear/anxiety in human Pavlovian B conditioning of heart rate (HR) responses. The conditioned stimuli (CSs) were phobia-relevant slides (snakes and spiders) and the unconditioned stimuli (UCSs) were aversive noises. The subjects were presented with two levels of noise intensity during acquisition and three levels of nonreinforced CS presentation (CS-only) in a delay differential (CS+/CS-) conditioning paradigm (2 x 3 x 2). Consistent with the incubation theory, conditioned HR acceleratory responses were sustained (resistance to extinction) for high-noise intensity and short-presentations of CS-only subjects. During the extinction phase, HR acceleratory responses quickly extinguished in low-noise intensity groups after the first presentations of CS-only. These findings were interpreted as support for the incubation theory of phobic fear.     

The role of nucleus accumbens dopamine in outcome encoding in instrumental and Pavlovian conditioning

Considerable evidence suggests that dopamine in the core subregion of the nucleus accumbens is not only involved in Pavlovian conditioning but also supports instrumental performance. However, it is largely unknown whether NAc dopamine is required for outcome encoding which plays an important role both in Pavlovian stimulus-outcome learning and instrumental action-outcome learning. Therefore, we tested rats with 6-hydroxydopamine (6-OHDA) induced dopamine depletion of the NAc core for their sensitivity to outcome devaluation in a Pavlovian and an instrumental task. Results indicate that 6-OHDA-lesioned animals were sensitive to outcome devaluation in an instrumental task. This finding provides support to the notion that NAc core dopamine may not be crucial in encoding action-outcome associations. However, during instrumental conditioning lever pressing rates in 6-OHDA-lesioned animals were markedly lower which could reflect an impaired behavioral activation. By contrast, after outcome-specific devaluation in a Pavlovian task, performance in 6-OHDA-lesioned animals was impaired, i.e. their magazine-directed responding was non-selectively reduced. One possibility to explain non-selective responding is that NAc core DA depletion impaired the ability of conditioned stimuli to activate the memory of the current value of the reinforcer.     

Pavlovian conditioning of shock-elicited aggression: a discrimination procedure

Two auditory stimuli, separated by a fixed intertrial interval, were alternately presented to two rats in a closed environment. The positive conditioned stimulus (CS+) terminated with the offset of a 2-mA, 0.75-sec shock. The negative conditioned stimulus (CS-) terminated without shock. The incidence of the "stereotyped fighting posture" was recorded during the CS+, the CS-, the intertrial interval, and shock. The results showed an increase in the percentage of conditioned responses during the CS+, and a decrease during both the CS- and the intertrial interval, when the duration of the conditioned stimuli and the intertrial interval was 16 sec. Appropriate changes in the incidence of aggression during the two stimuli were obtained following the reversal of the stimulus functions. During the acquisition and reversal phases there was a between-session decrement and a within-session improvement in the incidence of aggression during the CS+, defined as warm-up. The presentation of free shocks before the conditioning sessions was effective in reducing the warm-up only when the interval between shocks was 64 sec. These data were interpreted as demonstrating classical conditioning of shock-elicited aggression, with little chance of non-associative factors contributing to the measurement of the conditioned response.     

RWMODEL II: computer simulation of the Rescorla-Wagner model of Pavlovian conditioning

RWMODEL II simulates the Rescorla-Wagner model of Pavlovian conditioning. It is written in Delphi and runs under Windows 3.1 and Windows 95. The program was designed for novice and expert users and can be employed in teaching, as well as in research. It is user friendly and requires a minimal level of computer literacy but is sufficiently flexible to permit a wide range of simulations. It allows the display of empirical data, against which predictions from the model can be validated.     

The effects of conditioning and novelty on the rat's analgesic and pyretic responses to morphine

Six experiments with rat subjects investigated the role of conditioning in morphine tolerance. Concurrent assessments of body temperature and pain sensitivity were conducted. Experience with morphine produced tolerance to its analgesic effects but enhancement of its hyperthermic effects. Environmental novelty enhanced analgesia but not body temperature (Experiments 1 and 4). Under conditions in which a discriminated hyperthermic CR provided clear evidence that morphine-environment learning had developed, discriminated analgesic tolerance was not obtained (Experiments 2 and 3). Similarly, whereas placebo administrations extinguished the hyperthermic CR (Experiments 4 and 6), analgesic tolerance remained unaffected (Experiments 4, 5, and 6). These experiments suggest that the pyretic and analgesic systems are differentially sensitive to conditioning and the effects of novelty.     

Event representation in Pavlovian conditioning: image and action

In a typical Pavlovian conditioning experiment, a relatively insignificant event, the conditioned stimulus (CS), is paired with a biologically more meaningful event, the unconditioned stimulus (US). As a consequence of those pairings, the CS is thought to acquire response characteristics of the US. In this article I describe experiments with rats that suggest that under some circumstances, the CS acquires control of perceptual processing of the US, in the absence of that US itself. I present three kinds of evidence for this surrogate processing, which I liken to imagery or hallucination: (1) CSs come to control specific, sensory-evaluative responses normally evoked only by the USs; (2) CSs can substitute for USs in the establishment of new learning about those USs themselves; (3) CSs can substitute for USs in the modulation of conditioning to other events, either overshadowing (interfering) or potentiating learning, in the same manner as the USs themselves. Finally, I compare these data with evidence for conditioned sensation and imagery in humans, and suggest that imagery may be a very basic process, evolutionarily derived from perceptual and conditioning processes adapted to deal with remote or absent objects.     

Experimental extinction in Pavlovian conditioning: Behavioural and neuroscience perspectives

This paper reviews the behavioural and neuroscience literatures on extinction in Pavlovian conditioning with a view towards finding possible points of contact between these two often independent lines of investigation. Recent discoveries at the behavioural level indicate (1) that conditioned stimulus (CS)-unconditioned stimulus (US) associations specific in their sensory content are fully preserved during extinction, (2) that inhibitory stimulus-response associations appear to be learned during extinction, (3) that extinction is influenced by the level of activation of the US representation during nonreinforced trials, (4) that decreases in attention can influence conditioned performance during extinction, and (5) that contexts acquire an ability to modulate learning during both conditioning and extinction. Recent discoveries at the neural systems level suggest (1) that the hippocampus is important in context-specific learning during extinction, (2) that the prefrontal cortex is possibly important in long-term memory for extinction, (3) that the basolateral amygdala may be important in sustaining attention to a CS during extinction, (4) that NMDA receptors are important either in neural plasticity during extinction or by affecting the value of the US representation during extinction, and (5) that the GABAergic system may partially mediate inhibitory learning during extinction. It is concluded that both of these levels of analysis can benefit the other in the pursuit of a more comprehensive understanding of extinction.