Time course for development of benzodiazepine tolerance and physical dependence

Abstract

Chronic benzodiazepine treatment elicits adaptive responses in the CNS, seen behaviorally as functional tolerance and physical dependence. Experiments are described in which a radioreceptor assay is used to follow benzodiazepine activity in CSF samples during daily flurazepam treatment of cats. Tolerance is evident even after the second dose, despite increasing CSF drug activity, showing a large and rapidly developing functional tolerance. Other studies are discussed which also show tolerance within 24 hours of initiating benzodiazepine treatment. In contrast, a spontaneous withdrawal syndrome is usually seen only after prolonged treatment with high doses. However, physical dependence can also be studied by precipitating abstinence with a benzodiazepine antagonist, such as Ro15-1788. Cats were treated daily with flurazepam, then Ro15-1788 was given and abstinence signs were recorded. Abstinence could be precipitated 24 hours after beginning treatment, and dependence was nearly maximal after 7 days. Dependence developed during treatment with as little as 0.5 mg/kg flurazepam, which is near threshold for any behavioral response. Chronic diazepam caused the same dependence as flurazepam. Thus, the development of tolerance and physical dependence both show a remarkably rapid adaptation of the CNS in response to benzodiazepines.