Shepard Siegel

Classical Conditioning, Drug Tolerance, and Drug Dependence

Most theories of drug tolerance and dependence stress the physiological consequences of repeated pharmacological stimulation. There is considerable evidence, however, that the organism’s experience with the drug administration environment, as well as the drug, often importantly contributes to tolerance and dependence. The role of such environmental cues has been elaborated in a model which emphasizes Pavlovian conditioning principles. This account is based on the work of a number of investigators, but primarily Wikler (e.g., 1973, 1977, 1980), who have stressed the contribution of pharmacological learning to drug effects. This chapter describes the conditioning theory of tolerance, summarizes the data which supports the theory, discusses the relevance of the theory to drug dependence, and presents the implications ofthe theory for the treatment of drug abuse. Since some of the material has been summarized previously (Hinson and Siegel, 1980; Siegel, 1978a, 1979 b), this chapter emphasizes developments subsequent to earlier reviews.

Pharmacological Conditioning and Drug Effects

Typically, the effects of a drug, and alterations in these effects over the course of repeated administrations (i.e., tolerance and sensitization), have been attributed to wholly systemic mechanisms. For example, the effect of an exogenous opiate may be attributable to its effects at central endorphin receptors, and tolerance may be the result of the neurochemical alterations induced by repeated drug administrations. It has become apparent, however, that drug effects are importantly modulated by nonpharmacological factors. The result of the chemical stimulation depends not only on pharmacodynamic and pharmacokinetic principles, but also upon the recipient’s previous experiences and expectations.

The role of conditional drug responses in tolerance to the hypothermic effects of ethanol

The role of predrug cues in tolerance to ethanol-induced hypothermia was investigated in two experiments. The results of Experiment 1 demonstrated that tolerance was displayed only when the drug was administered in conjunction with environmental stimuli that had, in the past, accompanied ethanol administration. A conditional hyperthermic response was elicited when a placebo, instead of ethanol, was administered in conjunction with the usual ethanol cues. Results of Experiment 2 suggested that tolerance to ethanol-induced hypothermia can be extinguished by repeated placebo injections. These results indicate that associative processes, previously demonstrated to modulate opiate tolerance, also modulate ethanol tolerance.

The role of Pavlovian processes in drug tolerance and dependence: Implications for treatment

Abstract Evidence for the crucial role of Pavlovian conditional compensatory responses in tolerance to opiates and alcohol is presented. Furthermore, an analysis of the motivational role of Pavlovian conditional compensatory responses to craving and relapse is discussed, and supportive experimental and epidemiological evidence are presented. Given the role ascribed to Pavlovian processes in tolerance, craving, and relapse, it is proposed that extinction of cues which elicit conditional compensatory responses is an essential factor for treatment. Additionally, it is suggested that by virtue of prior Pavlovian conditioning, stress and depression may serve as cues to elicit conditional compensatory responses and attendant craving and these cues can also be extinguished by Pavlovian procedures. Finally, it is suggested that explication of this conditioning analysis to the patient may itself be an important cognitive adjunct to treatment.

Pavlovian psychopharmacology: the associative basis of tolerance.

The Pavlovian conditioning analysis of drug tolerance emphasizes that cues present at the time of drug administration become associated with drug-induced disturbances. These disturbances elicit unconditional responses that compensate for the pharmacological perturbation. The drug-compensatory responses eventually come to be elicited by drug-paired cues. These conditional compensatory responses (CCRs) mediate tolerance by counteracting the drug effect when the drug is administered in the presence of cues previously paired with the drug. If the usual predrug cues are presented in the absence the drug, the unopposed CCRs are evident as withdrawal symptoms. Recent findings elucidate intercellular and intracellular events mediating CCRs and indicate the importance of internal stimuli (pharmacological cues and interoceptive cues inherent in self-administration) to the acquisition of drug tolerance and the expression of withdrawal symptoms.

Conditioning insulin effects.

It has previously been demonstrated that after a number of insulin injections in rats, an injection of a placebo leads to an elevation in blood sugar. It has been suggested that this apparent conditioned compensatory response is an artifact resulting from stressing the subject (when large doses of insulin are used) or represents a nonassociative phenomenon (when small doses of insulin are used). These two suggestions were rejected on the basis of the results of Experiments 1 and 2, respectively. Experiments 3 and 4 demonstrated that although the behavioral effects of insulin can be conditioned to the injection procedure, such conditioned insulinlike behaviors (contrary to suggestions of many investigators) are not mediated by a pypoglycemic state.

The role of predrug signals in morphine analgesic tolerance: support for a Pavlovian conditioning model of tolerance.

According to a model of morphine tolerance, which emphasizes Pavlovian conditioning principles, tolerance results from an association between predrug environmental cues and the systemic effects of the drug. To assess this model, groups of rats were administered morphine on either three or nine occasions, with a complex environmental stimulus either paired or not paired with each injection. Control groups had equivalent experience with the environmental cue and injection procedure, but the injected substance was physiological saline. Subsequently, the analgesic effect of the opiate was tested in all subjects following administration of the drug in conjunction with the environmental cue. As expected on the basis of the conditioning model of tolerance, subjects with a pretest history of paired morphine administrations displayed analgesic tolerance, but subjects with a pretest history of unpaired administration displayed no evidence of such tolerance. The results suggest that prior demonstrations that the display of morphine tolerance is specific to the drug administration environment may be readily interpreted by a conditioning analysis of tolerance.

Applying Laboratory Research: Drug Anticipation and the Treatment of Drug Addiction

Basic research concerning drug tolerance and withdrawal may inform clinical practice, and vice versa. Three areas that integrate the work of the laboratory and the clinic are discussed: (a) drug overdose, (b) cue exposure treatment of addiction, and (c) pharmacological treatment of withdrawal symptoms. The areas are related in that they indicate the contribution of drug-paired cues to the effects of addictive drugs and the role of Pavlovian conditioning of drug effects in drug tolerance and withdrawal symptoms.

Backward conditoning as an inhibitory procedure

Abstract Four independent groups of subjects received classical conditioning acquisition following exposure to the CS, the US, both in a noncontingent manner, or both in a backward-paired manner (the US always immediately preceding the CS). A fifth group received no preconditioning experience with the conditioning stimuli. In both the conditioned suppression situation with rats (Experiment 1) and the eyelid conditioning situation with rabbits (Experiment 2), preconditioning experience with the conditioning stimuli retarded acquisition. This retardation was most pronounced in subjects which had preexposure to the CS and the US in a backward-paired manner, suggesting that the backward contingency produced inhibitory tendencies in excess of those expected simply on the basis of any nonassociative effects of adaptation to the CS and US.

The widespread influence of the Rescorla-Wagner model

The theory of Pavlovian conditioning presented by Robert Rescorla and Allan Wagner in 1972 (the Rescorla-Wagner model) has been enormously important in animal learning research. It also has been applied in a variety of areas other than animal learning. We summarize the contribution of the Rescorla-Wagner model to research in verbal learning, social psychology, human category learning, human judgments of correlational relationships, transitive inference, color aftereffects, and physiological regulation. We conclude that there have been few models in experimental psychology as influential as the Rescorla-Wagner model.