The history of benzodiazepine dependence: a review of animal studies.

This article provides a historical review of the animal literature relating to the development of tolerance to the behavioral effects of benzodiazepines, and the incidence of biochemical and behavioral changes that result from termination of benzodiazepine treatment (spontaneous withdrawal responses). It charts the slow emergence of a pertinent animal literature and highlights conclusions that were prevalent in 1963 (at the introduction of diazepam), 1973 (at the introduction of lorazepam), 1980 and the present day. For 25 years the animal literature has lagged behind the clinical literature, but recent studies into the neurochemical mechanisms of benzodiazepine dependence and possible treatments for withdrawal responses suggest that, at last, animal experiments may be about to make a substantial contribution.