A simple and rapid method of inducing physical dependence with benzodiazepines in mice

Physical dependence was rapidly induced in mice by administering diazepam intraperitoneally twice daily using an incremental dosing regimen (50 to 450 mg/kg) for nine consecutive days. Withdrawal was induced (24 hr after the last dose) by administration of a benzodiazepine antagonist, RO-15-1788 (10 mg/kg, IP). All of the mice exhibited clear-cut withdrawal symptoms (i.e., convulsions) within minutes of antagonist treatment. This method offers a simple, reliable, high throughput procedure for the assessment of benzodiazepine-like physical dependence liability and withdrawal, and it would be useful for screening purposes.