Precipitated diazepam withdrawal in baboons: effects of dose and duration of diazepam exposure

Baboons were exposed to diazepam via continuous injection at doses of 0.125-20.0 mg/kg per day intragastrically (i.g.) for 7 days or to 20 mg/kg per day, i.g. for 1 h or 1 to 35 days. After diazepam administration, Ro 15-1788, a benzodiazepine antagonist was given (5.0 mg/kg i.m.) and precipitated benzodiazepine withdrawal was evaluated by scoring individual signs. The severity of the withdrawal, as indicated by the number of the different signs as well as by frequency of individual signs, increased as the dose and duration of diazepam exposure were increased. Consistent elevations in diazepam withdrawal signs were evident after a dose as low as 0.25 mg/kg per day for 7 days and after administration of 20 mg/kg per day for as short as 3-7 days. Data also suggested that history of previous benzodiazepine exposure sensitized animals to subsequent development of physical dependence. Overall, this study suggests that benzodiazepines produce meaningful functional changes in the central nervous system after exposure to relatively low doses and after relatively short durations of exposure.