Tolerance often depends on experience with drug administration cues as well as on the drug. A way of characterizing the role of predrug cues in tolerance is to emphasize the importance of drug expectation in drug effects: tolerance is maximally displayed following expected drug administration, but not following unexpected drug administration. The contribution of drug expectancy to tolerance has been incorporated in a Pavlovian conditioning model. Many pharmacological conditional responses (CRs) are opposite to the pharmacological unconditional response (UCR). These drug-anticipatory CRs increasingly attenuate the UCR over the course of successive administrations, thus contributing to tolerance. Support for the conditioning analysis is provided by demonstrations that animals with a history of opiate administration display both tolerance when administered the drug and compensatory responding when administered a placebo, when these substances are presented in the context of the usual predrug cues; neither tolerance nor CRs are displayed in the context of alternative cues. Further evidence that Pavlovian conditioning contributes to tolerance is provided by demonstrations that nonpharmacological manipulations of the putative conditional stimulus (i.e., environmental cues present at the time of drug administration), known to affect the acquisition of a variety of CRS, similarly affect the acquisition of tolerance.
