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Conditioned Tolerance


Tolerance refers to the diminishment or the loss of a drug effect over the course of repeated administrations. Some researchers have postulated that an important factor in the development of tolerance is Pavlovian conditioning of drug-compensatory responses. The administration of a drug may be viewed as a Pavlovian conditioning trial. The stimuli present at the time of drug administration are the conditional stimulus (CS), while the effect produced by the drug is the unconditional stimulus (UCS). Many drug effects involve disruption of the homeostatic level of physiological systems (e.g., alcohol lowers body temperature), and these disruptions elicit compensatory responses that tend to restore functioning to normal levels. The compensatory, restorative response to a drug effect is the unconditional response (UCR). Repeated administrations of a drug in the context of the same set of stimuli can result in the usual predrug cues coming to elicit as a conditional response (CR) the compensatory, restorative response. The conditional drug-compensatory CR would tend to reduce the drug effect when the drug is administered with the usual predrug cuesthus accounting for tolerance, or at least some aspects of tolerance.

One test of the Pavlovian conditioning model of tolerance is whether conditional drug-compensatory responses are elicited by predrug cues. In one experiment with rats (Crowell, Hinson, & Siegel, 1981), injections of alcohol in the context of one set of stimuli were alternated with injections of saline solution in the context of a different set of stimuli for several days. Each day, the rats' body temperatures were measured. Alcohol lowered body temperatures the first time it was given, but this effect diminished over the course of the repeated alcohol administrationsthat is, tolerance developed to the hypothermic effect of alcohol. To determine if a drug-compensatory CR was elicited by the usual predrug cues, the rats were given a placebo CR test. In a placebo CR test, saline solution is administered instead of the drug. The placebo CR test was given to some rats under conditions where they were expecting alcohol; that is, saline was administered with the usual predrug cues. For the remaining rats, the placebo CR test was given under conditions where there should have been no expectancy of alcohol, that is saline was administered with cues that had previously signaled only saline. Rats given saline with the usual predrug cues had elevated body temperatures, while rats given saline without the usual predrug cues showed little temperature change. Thus, it was possible to directly observe the drug-compensatory CR, in this case hyperthermia opposed to the hypothermic effect of alcohol. Other experiments similar to the one just described have found drug-compensatory CRs following the development of tolerance to various effects of Opiates, Barbiturates, and Benzodiazepines (Siegel, 1983).

Conditioned responses occur only when the conditional stimulus is presented. If drug-compensatory CRs contribute to tolerance, then tolerance should only be evident in the presence of the usual predrug cues that are the CS. This expectation was tested in the experiment by Crowell, Hinson, and Siegel (1981), involving tolerance to the hypothermic effect of alcohol. After all rats had developed tolerance to the hypothermic effect of alcohol, a test was given in which some rats received alcohol with the usual predrug cues, while other rats received alcohol when the usual predrug cues were not present. Although all rats had displayed tolerance prior to the test, only those rats given alcohol in the presence of the usual predrug cues (i.e., with the CS) showed tolerance during the test. The explanation of this "situational specificity" of tolerance is that when alcohol is given with the usual predrug cues, the drug-compensatory CR occurs and reduces the drug effectbut when alcohol is given without the usual predrug cues, the drug-compensatory CR does not occur and the drug effect is not reduced. Other research has demonstrated situational specificity with regard to tolerance to opiates, barbiturates, and benzodiazepines (for a complete review see Siegel, 1983).

In order to eliminate a CR, it is necessary to present the CS not followed by the UCS, a procedure termed extinction. Research indicates that the loss of tolerance occurs as a result of extinction of drug-compensatory CRs. Again referring to the experiment of Crowell, Hinson, and Siegel (1981), rats were given alcohol in the presence of a consistent set of cues until tolerance developed. Then, all drug injections were stopped for several days. During this period some animals were given extinction trials, in which the usual predrug cues were presented but only saline was injected. The other animals did not receive extinction trials and were left undisturbed during this time. Subsequently, all animals were given a test in which the drug was given with the usual predrug cues. The animals that had received extinction trials were no longer tolerant, whereas animals that had not been given extinction trials retained their tolerance. Similar resultsin which tolerance is retained unless extinction trials are givenoccur for tolerance to opiates, barbiturates, and benzodiazepines (Siegel, 1983).

The drug-compensatory CRs that contribute to tolerance may also be involved in withdrawal-like symptoms that occur in detoxified drug addicts. Detoxified addicts often report experiencing withdrawal-like symptoms when they return to places where they formerly used drugs, although they are now drug free. The places where the addict formerly used drugs act as CSs and still elicit drug-compensatory CRs; even when the addict is drug free, the drug-compensatory CRs achieve expression. Thus, it is postulated that the drug-compensatory CRs elicited by the usual predrug cues in the drug-free postaddict result in a withdrawal-like syndrome (Hinson & Siegel, 1980). This conditional postdetoxification withdrawal syndrome may motivate the postaddict to resume drug taking (to alleviate the symptoms).

(See also: Addiction: Concepts and Definitions ; Causes of Drug Abuse: Learning ; Tolerance and Physical Dependence ; Wikler's Pharmacologic Theory of Drug Addiction )


Crowell, C., Hinson, R. E., & Siegel, S. (1981). The role of conditional drug responses in tolerance to the hypothermic effects of alcohol. Psychopharmacology, 73, 51-54.

Hinson, R. E., & Siegel, S. (1980). The contribution of Pavlovian conditioning to ethanol tolerance and dependence. In H. Rigter & J. C. Crabbe (Eds.), Alcohol tolerance and dependence. Amsterdam: Elsvier/North Holland Biomedical Press.

Siegel, S. (1983). Classical conditioning, drug tolerance, and drug dependence. In F. B. Glaser et al. (Eds.), Research advances in alcohol and drug problems, vol. 7. New York: Plenum.

Riley Hinson

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