Anxiogenic effects in benzodiazepine withdrawal are linked to the development of tolerance

Rats were tested in the elevated plus-maze test of anxiety after a probe injection of chlordiazepoxide (CDP 5 mg/kg) following short-term (5 days) or long-term (20 days) pretreatment with 5 or 20 mg/kg/day. After short-term pretreatment with either dose, the probe dose had anxiolytic effects (it increased the % number of entries, and % of time spent, on the open arms). After long-term pretreatment with either dose of CDP there was tolerance to these effects. When the rats were tested 24 hours after their last dose of CDP, there was no indication of spontaneous withdrawal responses in the rats from the short-term pretreatment groups, but the rats in the long-term pretreatment groups showed increased anxiety (decreases in the % number of entries, and the % of time spent, on the open arms, compared with controls). These results support suggestions that the development of tolerance and the incidence of withdrawal anxiety may both be manifestations of the underlying changes occurring during drug dependence.