Homeostasis is by many investigators regarded to be the mechanism responsible for the development of tolerance to drugs. In this paper it is demonstrated that homeostasis does not describe this effect sufficiently. The adaptive behaviour of regulated systems the main factor in the development of drug tolerance - is shown to be much more complex than homeostasis can describe. It is stressed that the behaviour of complex regulated mechanisms can be understood only with the help of mathematical models. The concept underlying a mathematical model of the development of tolerance to drugs is presented. The model gives a description of drug tolerance, drug dependence and drug addiction and establishes a relation between the rapid action of drugs and the slow build up of tolerance. The model makes use of memory to account for the slow build up of tolerance during successive administrations of a drug. It is made plausible that the organism is able to recognize a drug at the moment it is applied, before it exerts its effect upon the organism. It is shown that the mechanism responsible for the suppression of the drug effect, is also the cause of the reaction of the organism when the drug effect has ceased and of the much larger reactions which follow when a drug is withdrawn after addiction has developed. These effects are adequately described by the model as well as the involvement of environmental cues and the role of the central nerve system, providing a comprehensive description of the process of tolerance development and addiction. (A)
Abstract