Effects of the 5-HT3 antagonist ondansetron on benzodiazepine-induced operant behavioural dependence in rats

This study was designed to assess whether rats made tolerant to the suppressant action on Fixed Ratio operant responding of the benzodiazepine (BZ) chlordiazepoxide (CDP) would show behavioural disruption on drug withdrawal—so-called operant behavioural dependence. In addition, the study examined the effects of the 5-HT₃ antagonist ondansetron on such operant behavioural dependence. During 42 consecutive days of CDP treatment, at deses escalated from 10 to 30 mg/kg/day, marked tolerance developed to the rate-suppressant action of CDP. On subsequent days, during spontaneous withdrawal, response rates declined significantly by around 30% in animals treated with saline, although some recovery of responding was seen over successive days of withdrawal. Similar reductions in responding followed by recovery were seen in rats treated with the 5-HT₃ antagonist ondansetron (0.01–0.1 mg/kg, b.i.d.). These findings demonstrate for the first time that it is possible to use operant procedures to detect spontaneous BZ withdrawal. They also suggest, in agreement with recent studies from this laboratory (Leathley and Goudie 1992), that 5-HT₃ antagonists may have relatively limited utility in treating some signs of BZ dependence.