Occasion setting and drug tolerance

There is considerable evidence that drug-paired cues become associated with drug effects. It has been hypothesized that these cues act as Pavlovian conditional stimuli (CSs), and elicit conditional compensatory responses that contribute to tolerance. On the basis of a conditioning analysis of tolerance, we would expect that is should be possible to establish drug-paired cues as occasion setters, as well as conditional stimuli. Using feature-positive discrimination training, we evaluated the contribution of occasion-setting stimuli (as well as CSs) to tolerance to the hypothermic effect of ethanol in rats. The results indicated that a complete associative analysis of drug tolerance should incorporate not only the CS properties of predrug cues, but also the occasion-setting properties of such cues. The findings have implications for interpreting conflicting findings concerning extinction of tolerance and for cue-exposure treatments of addiction.     

Drug Tolerance, Drug Addiction, and Drug Anticipation

ABSTRACT— Environmental cues associated with drugs often elicit withdrawal symptoms and relapse to drug use. Such cues also modulate drug tolerance. The contribution of drug-associated stimuli to withdrawal and tolerance is emphasized in a Pavlovian-conditioning analysis of drug administration. Conditional responses occur in the presence of cues that have been associated with the drug in the past, such as the setting in which the drug was taken. These conditional responses mediate the expression of tolerance and withdrawal symptoms. Recently, it has become apparent that internal predrug cues, as well as environmental cues, elicit pharmacological conditional responses that contribute to tolerance and withdrawal. Such internal cues include cognitive or proprioceptive cues incidental to self-administration, drug-onset cues that are experienced shortly after administration, and emotional cues. According to the conditioning analysis, addiction treatment should incorporate learning principles to extinguish the association between stimuli (environmental and internal) present at the time of drug administration and the effects of the addictive drug.     

Drug-onset cues as signals: intraadministration associations and tolerance.

On the basis of a conditioning analysis of drug tolerance, drug-associated cues become associated with the drug effect. These cues elicit conditional compensatory responses and modulate the expression of tolerance. Although there are many findings consistent with the conditioning analysis of tolerance, there also are contrary findings. The results of these experiments suggest that some of the apparently contradictory findings result because interoceptive pharmacological cues, as well as exteroceptive environmental cues, are paired with a drug effect. That is, within each administration, early drug-onset cues may become associated with the later, larger drug effect, and these pharmacological cues may overshadow simultaneously present environmental cues. We demonstrate the contribution of such intraadministration associations to tolerance to the analgesic effect of morphine and to the expression of conditional compensatory hyperalgesia.     

Intraadministration associations: conditional hyperalgesia elicited by morphine onset cues

There is evidence that exteroceptive cues associated with drug administration elicit conditional compensatory responding (e.g., hyperalgesia in organisms with a history of morphine administration). Recently it has become apparent that, within each administration, interoceptive early-drug onset cues (DOCs) may become associated with the later, larger drug effect (intraadministration associations). The present experiments evaluated DOC-elicited conditional hyperalgesia in rats intravenously infused with morphine. The results indicated that DOC-elicited hyperalgesia contributes to tolerance to the analgesic effect of morphine, and such DOC-elicited hyperalgesia is an associative phenomenon, rather than a sensitized response to the opiate. The findings suggest that associative analyses of tolerance should acknowledge the conditional responding elicited by DOCs, and extinction-based addiction treatments should incorporate extinction of DOC-elicited conditional responding.     

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.     

The role of drug expectancy in the control of human drug seeking

Human drug seeking may be goal directed in the sense that it is mediated by a mental representation of the drug or habitual in the sense that it is elicited by drug-paired cues directly. To test these 2 accounts, the authors assessed whether a drug-paired stimulus (S+) would transfer control to an independently trained drug-seeking response. Smokers were trained on an instrumental discrimination that established a tobacco S+ in Experiment 1 and a tobacco and a money S+ in Experiment 2 that elicited an expectancy of their respective outcomes. Participants then learned 2 new instrumental responses, 1 for each outcome, in the absence of these stimuli. Finally, in the transfer test, each S+ was found to augment performance of the new instrumental response that was trained with the same outcome. This outcome-specific transfer effect indicates that drug-paired stimuli controlled human drug seeking via a representation or expectation of the drug rather than through a direct stimulus-response association.     

Occasion-setting training renders stimuli more similar: Acquired equivalence between the targets of feature-positive discriminations

In two experiments rats received training on two concurrent appetitive feature-positive discriminations. A preliminary test in Experiment 1 confirmed previous demonstrations of the transfer of occasion-setting properties—the feature from one of these discriminations was better able to facilitate responding to the occasion-set target CS from the second discrimination than to a control stimulus that had not been the subject of occasion-setting. The source of this transfer was investigated in a second phase of training, and in Experiment 2. In both experiments one of the occasion-set CSs was paired with food, and generalization of appetitive conditioned responding from this stimulus to the second occasion-set CS, and to a control cue, was examined. There was more generalization from the first occasion-set CS to the second CS that had also been occasion-set than to the control cue. This is taken as evidence that occasion-set CSs are rendered more similar as a result of their common training history. The implications of these findings for explaining transfer of occasion setting are discussed.     

Development of intersensory function: age-related differences in stimulus selection of multimodal compounds in rats as revealed by Pavlovian conditioning.

Preweanling and adult rats were exposed to Pavlovian stimulus pairings with lights, tones, and light-tone compounds as conditional stimuli (CSs). Tone intensity was varied. As was found in previous studies using flavor CSs, odor CSs, or both, in which significant overshadowing or potentiation occurred to an element of a compound, overshadowing was less likely and potentiation more likely for preweanlings than for adults. Several experiments supported the view that these effects reflect an age-related difference in the controlling properties of stimuli: Young rats are more disposed to encode multimodal compounds on the basis of amodal intensity, whereas their elders are more likely to encode modality-specific properties of light and sound. Differential reinforcement in the presence of lights, tones, and light-tone compounds made preweanlings' stimulus selection appear more adultlike and may be a cause of development of intersensory function.     

Second-order olfactory-mediated fear-potentiated startle

Recently, we reported that discrete (4-sec) olfactory cues paired with footshock serve as effective conditioned stimuli (CSs) for potentiating the acoustic startle response in rats using the fear-potentiated startle paradigm. Because odors are such salient cues for the rat, and because of the robust olfactory conditioning observed previously, the current studies investigated second-order fear conditioning using olfactory and visual cues. In Experiments 1 and 2, we used a small number of first-order and second-order training trials on separate days to investigate second-order fear-potentiated startle. Significant potentiated startle was observed in animals receiving Paired/Paired training in both studies, but surprisingly, control animals in the Unpaired/Paired group (Exp. 1) also showed significant potentiated startle to a light S2 at testing. These findings are addressed in the Discussion. Overall, the results of both experiments suggest that olfactory cues serve as efficient S1 and S2 stimuli in second-order fear-potentiated startle paradigms when only a small number of first and second-order training trials are presented.     

Post-retrieval beta-adrenergic receptor blockade: effects on extinction and reconsolidation of cocaine-cue memories

Contexts and discrete cues associated with drug-taking are often responsible for relapse among addicts. Animal models have shown that interference with the reconsolidation of drug-cue memories can reduce seeking of drugs or drug-paired stimuli. One such model is conditioned place preference (CPP) in which an animal is trained to associate a particular environment with the rewarding effects of a drug. Previous work from this laboratory has shown that intra-nucleus accumbens core infusions of a MEK inhibitor can interfere with reconsolidation of these drug-cue memories. A question that remains is whether post-retrieval drug effects on subsequent memories represent an interference with reconsolidation processes or rather a facilitation of extinction. In this experiment, we explore the effect of post-retrieval injections of propranolol, a beta-adrenergic receptor antagonist, on reconsolidation and extinction of cocaine CPP. After acquisition of cocaine CPP, animals were given post-retrieval propranolol injections once or each day during a protocol of unreinforced preference tests, until the animals showed no preference for the previously cocaine-paired environment. Following a cocaine priming injection, the animals that received daily post-test propranolol injections did not reinstate their preference for the drug-paired side. In contrast, a single post-retrieval propranolol injection followed by multiple days of unreinforced preference tests failed to blunt subsequent cocaine reinstatement of the memory. These data suggest that daily post-retrieval systemic injections of propranolol decrease the conditioned preference by interfering with reconsolidation of the memory for the association between the drug-paired side and the reinforcing effects of the drug, rather than facilitating new extinction learning.     

Evaluation of the relation between Pavlovian occasion-setting and instrumental discriminative stimuli: a blocking analysis

Experiments with rat subjects used a blocking design (A+, then AB+) to assess the relation between Pavlovian occasion-setting and instrumental discriminative stimuli. Prior conditioning of both associative and occasion-setting functions of A in a serial feature-positive procedure blocked acquisition of an instrumental discriminative function by a novel stimulus (B) trained in compound with A. However, neither prior conditioning of only an A-US (unconditioned stimulus) association nor prior conditioning of Stimulus A using a Pavlovian simultaneous feature-positive procedure, which does not endow A with an occasion-setting function, blocked acquisition of an instrumental discriminative function by B. Prior acquisition of an instrumental discriminative function by A blocked acquisition of a Pavlovian occasion-setting function by a novel stimulus (B) trained in compound with A, but did not block acquisition of an association between B and the US. These outcomes indicate that Pavlovian occasion-setting and instrumental discriminative properties of a stimulus are functionally equivalent and that both Pavlovian occasion-setting and instrumental discriminative properties of a stimulus are functionally independent of simple associative relations between that stimulus and other events.     

The effects of satiation after first— and second-order appetitive conditioning in rats

Rats received first- and second-order conditioning based on a food unconditional stimulus (US). The effects of postconditioning satiation on the performance of detailed behavioral components of general activity evoked by first- and second-order conditional stimuli (CSs) were then assessed in extinction tests. Satiation reduced the frequency of all components of general activity evoked by first-order CSs but had little or no effects on behaviors evoked by second-order CSs. These results are consistent with earlier suggestions that first-but not second-order conditional responding is mediated by a representation of the US and that a major effect of satiation is to devalue that representation.     

Self-administration cues as signals: drug self-administration and tolerance

There is evidence that drug-associated exteroceptive cues elicit compensatory conditional responses (CCRs) that contribute to tolerance. The authors evaluated whether interoceptive, self-administration cues (SACs) similarly contribute to tolerance. In Experiments 1 and 2, the ataxic effect of ethanol was measured in rats that self-administered (SA) ethanol--by either oral consumption or intragastric infusion--and in rats that were yoked (Y) to these self-administrators. In both experiments, the ataxic effect of ethanol was more pronounced in Y than in SA rats. In addition, SA rats failed to display usual levels of tolerance when ethanol was administered in the absence of SACs and displayed a CCR of hypertaxia in response to SACs not followed by ethanol. The results of Experiment 3 indicate that the ataxic effect of intravenous heroin also was greater in Y than in SA rats. The findings suggest that SACs contribute to drug tolerance.     

The Rescorla-Wagner model: losses in associative strength in compound conditioned stimuli

This series of experiments demonstrated that compound conditioned stimuli (CSs) highly conditioned in isolation lose conditioned response strength when compound-CS-unconditioned stimulus (US) pairings are given. This loss in conditioned responding was a positive function of the number of compound-CS-US pairings and was greater for the more salient stimulus. Finally, if a previously neutral stimulus was compounded with two previously conditioned cues, the neutral stimulus could acquire conditioned inhibitory properties with only compound-CS-US pairings. These results provide support for some aspects of the Rescorla-Wagner model.     

Responding in configural discrimination problems depends on density of reinforcement in time

Previous research has shown that conditioned responding in differential skin conductance conditioning increased for reinforced stimuli (CSs+) but remained constant for nonreinforced stimuli (CSs-) due to decreasing reinforcement density. The present two experiments (Experiment 1: Negative patterning; Experiment 2: Positive patterning) were designed to disentangle a possible confound of reinforcement density with stimulus frequency. In order to achieve this, we varied the intertrial interval (18 s, 24 s, or 48 s) and held constant the numbers of CSs+ and of CSs- in each of both discrimination problems. With increasing intertrial intervals, we found higher responding both to CSs+ and to CSs- as well as increased response differentiation. We discuss these results with respect to two mechanisms offered by Wagner's SOP model and conclude that the observed effects are due to variations in density of reinforcement in time.     

The renewal of extinguished conditioned fear with fear-relevant and fear-irrelevant stimuli by a context change after extinction

The acquisition, extinction, and subsequent recovery of conditioned fear can be influenced by the nature of the conditional stimulus (CS) and the context in which the CS is presented. The combined effects of these factors were examined in a differential fear-conditioning procedure with humans. Fear-relevant or fear-irrelevant CSs were followed by a shock unconditional stimulus (US) during acquisition and presented alone during extinction. The CSs were images presented upon different background contexts. Half the participants received the same context during acquisition and extinction and the remaining received different contexts. All participants received test trials in the same context as acquisition. In Experiment 1 (N=64), a renewal of shock expectancy and skin conductance responses was found during test for fear-relevant and fear-irrelevant CSs when extinction was given in a different context. In Experiment 2 (N=72), renewal for fear-relevant stimuli was enhanced when acquisition and test was given in an indoor office context and extinction in an outdoor bush context. The opposite context configuration produced the strongest renewal for fear-irrelevant stimuli. The return of extinguished conditioned fear can occur to fear-relevant stimuli that are commonly associated with clinical fears and its strength may be enhanced when the stimuli are encountered in certain contexts after extinction.     

Conceptual similarity promotes generalization of higher order fear learning

We tested the hypothesis that conceptual similarity promotes generalization of conditioned fear. Using a sensory preconditioning procedure, three groups of subjects learned an association between two cues that were conceptually similar, unrelated, or mismatched. Next, one of the cues was paired with a shock. The other cue was then reintroduced to test for fear generalization, as measured by the skin conductance response. Results showed enhanced fear generalization that correlated with trait anxiety levels in the group that learned an association between conceptually similar stimuli. These findings suggest that conceptual representations of conditional stimuli influence human fear learning processes.     

Contextual conditional discriminations

Three experiments used a discriminated operant procedure to study conditional discrimination learning in rats. The first experiment showed that rats were capable of learning a biconditional discrimination in which two contexts served as conditional cues signalling the reinforcement contingencies associated with two discriminative stimuli. The discrimination was learned equally well when one discriminative stimulus signalled food, the other its absence, and when one stimulus signalled food, the other extinction plus mild footshock.

In Experiment 2 it was shown that prior training on such a conditional discrimination enhanced the subsequent context specificity of simple conditioning relative to control groups of animals for whom the prior training had not been conditional. Experiment 3 showed that a reversal of the significance of one pair of discriminative stimuli produced no spontaneous reversal in performance to a second, target, pair.

The pattern of results is best accounted for by an analysis of contextual conditional discrimination learning in terms of stimulus configurations and offers no support for the notion that rats may learn a general conditional rule or set.     

Perceptual load alters visual excitability

Increasing perceptual load reduces the processing of visual stimuli outside the focus of attention, but the mechanism underlying these effects remains unclear. Here we tested an account attributing the effects of perceptual load to modulations of visual cortex excitability. In contrast to stimulus competition accounts, which propose that load should affect simultaneous, but not sequential, stimulus presentations, the visual excitability account makes the novel prediction that load should affect detection sensitivity for both simultaneous and sequential presentations. Participants fixated a stimulus stream, responding to targets defined by either a color (low load) or color and orientation conjunctions (high load). Additionally, detection sensitivity was measured for a peripheral critical stimulus (CS) presented occasionally. Increasing load at fixation reduced sensitivity to the peripheral CSs; this effect was similar regardless of whether CSs were presented simultaneously with central stimuli or during the (otherwise empty) interval between them. Controls ruled out explanations of the results in terms of strategic task prioritization. These findings support a cortical excitability account for perceptual load, challenging stimulus competition accounts.