A liquid diet model of chlordiazepoxide dependence in mice

Mice fed chronically (3 to 4 weeks) a liquid diet containing chlordiazepoxide (CDP) became physically dependent on the drug as demonstrated by the occurrence of withdrawal signs precipitated by injection of the benzodiazepine antagonist Ro15-1788 (5 to 25 mg/kg) or by omitting CDP from the diet (spontaneous withdrawal). Very low blood concentrations of CDP, but medium to high levels of the active metabolites N-desmethyl CDP and demoxepam were found during the period of CDP administration. The Ro15-1788-induced withdrawal signs appeared within 1 min after the injection of the antagonist and lasted for at least 10 min. Quantifiable withdrawal signs included tail lift, tremor, impaired movement and handling-induced seizures. Mice undergoing spontaneous withdrawal had milder withdrawal signs such as weight loss, in appetite and suppression of runway and head-dipping activities on day 1 or day 2 of withdrawal. These signs were also present in Ro15-1788-induced withdrawal. A long-lasting rebound increase in runway and head-dipping activities occurred several days after CDP withdrawal.