The authors presented a model that extrapolates the biological consequences of drug administration to account for acute and chronic tolerance. Drug-induced changes of regulated parameters provide detectable perturbations to which the brain responds. With experience, these centrally mediated responses are learned and can be activated in the absence of the drug-induced perturbation. Although neural responses following drug administration are often obscured, the model shows how these responses may be identified and provides a reinterpretation of drug conditioning paradigms. The authors made comparisons between the present empirical model of drug administration and existing theories of drug tolerance. The authors also presented a unified framework for understanding the consequences of repeated drug use and made specific predictions as to the relationships among acute and chronic tolerance, drug sensitization, and individual differences in vulnerability to drug addiction.