Tolerance to drugs acting as discriminative stimuli.

The experiments described above highlight the ways behavioral and pharmacodynamic processes interact to modulate the development of tolerance to the discriminative stimulus effects of drugs. These studies suggest that frequent drug exposure does not lead inevitably to the development of tolerance to a drug's discriminative effects. Rather, the interplay between a drug stimulus and reinforcement opportunities shapes the sensitivity of discriminative performances over successive episodes of drug exposure. Maintaining a discriminative relation between a drug and behavior strengthens the likelihood that an initially effective dose will maintain discriminative control. Development of tolerance requires exposure to both treatment regimens appropriate to the agent under study and behavioral contingencies that limit an individual's ability to learn a new discrimination. When both requirements are met, tolerance does develop to drugs acting as discriminative stimuli. When training is suspended during a period of chronic drug treatment, the dose of drug required to evoke stimulus control can be increased by treatment with appropriate maintenance doses of the training drug or a closely related drug. Tolerance is proportional to maintenance dose, develops relatively slowly, and disappears after termination of repeated drug treatment. Tolerance appears pharmacologically specific and can be accompanied by cross-tolerance to other drugs that evoke cross-generalization with the training drug. Finally, tolerance can be diminished markedly by continuing training with the original training dose. Taken together, these patterns suggest that development of tolerance to drugs acting as discriminative stimuli is the result of joint actions of conditioning and pharmacodynamic processes.