Homeostatic theory of drug tolerance: a general model of physiological adaptation.

At the heart of homeostatic theory is the idea that explicit or implicit behavioral demands placed on physiological systems are required for the biological detection of homeostatic disturbances. The detection of drug-induced disturbances is required to drive the development of all systemic tolerance, both associative and nonassociative (i.e., both forms of tolerance are behaviorally contingent). A wide range of findings ranging from morphine-induced analgesia to ethanol-induced hyposexuality shows that contingent tolerance is pervasive and may be universal. The theory also stipulates that behavioral demands placed on the target system will govern the loss of both associative and nonassociative tolerance (physiological). The present formulation integrates contingent, associative, and nonassociative tolerance and drug-opposite withdrawal reactions within a unified theory.