Sarmazenil-precipitated withdrawal: a reliable method for assessing dependence liability of benzodiazepine receptor ligands.

The benzodiazepine receptor partial inverse agonist sarmazenil exhibits in vivo proconvulsive, but not convulsant, effects in different paradigms in rodents. Intravenous sarmazenil challenge given at several fixed intervals following the termination of repeated treatment with a markedly sedative dose of diazepam in squirrel monkeys was effective in precipitating withdrawal signs, but had no comparable effects in vehicle-treated controls. The precipitated withdrawal reaction was not only robust, but it was consistently observed in all of the diazepam-treated monkeys. Thus, the use of sarmazenil challenge in the precipitated withdrawal paradigm provides a reliable method for assessing the development of physical dependence during repeated treatment with benzodiazepine receptor agonists.