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Receptor regulation as a unitary mechanism for drug tolerance and physical dependence--not quite as simple as it seemed!

This review examines the development of the unitary hypothesis that both drug tolerance and the drug withdrawal syndrome arise from adaptive regulation of drug receptors in the brain. Although there is still considerable merit in this hypothesis, the author explains that careful evaluation of some of the changes that have been reported suggests that many of these are not good explanations for both aspects of drug dependence. In addition, modern developments in the understanding of receptor mechanisms show that the original hypothesis represents a gross oversimplification of the true situation. Adaptive changes in post-receptor mechanisms are now believed to be at least as important as alterations in the receptors themselves. Equally some receptor proteins, by altering their subunit composition, may be able to adapt to the presence of drugs without producing major changes in the action of the natural transmitter. In conclusion, receptor regulation still seems to play an important role in drug dependence but this role is more complex than was once believed.