Attenuation of benzodiazepine withdrawal anxiety in the rat by serotonin antagonists

Administration of benzodiazepines is known to be associated with tolerance and a withdrawal syndrome on abrupt cessation. The aetiology of the withdrawal syndrome is not known but a role for the serotonin (5HT) system is suspected. The aim of the current study was to investigate the usefulness of 5-HT2 antagonists in the treatment of benzodiazepine withdrawal syndrome in the rat. Male Wistar rats were treated with either diazepam (4 mg/kg) or vehicle for 14 days, then abruptly withdrawn for 24 h. Animals were tested in the social interaction paradigm and elevated plus maze. Some diazepam-withdrawn rats were pre-treated with 5HT2 antagonists 60 min before behavioural testing. Acute withdrawal from benzodiazepines significantly reduced social interaction between pairs compared to vehicle or diazepam-treated animals. Similarly, for the elevated plus maze withdrawn animals made fewer entries and spent less time on the open arms than did vehicle or diazepam-treated animals. Single doses of 5-HT2 antagonists, mianserin (5 mg/kg) and ritanserin (1 mg/kg), effectively ameliorated withdrawal anxiety in the rat, returning behavioural function in the social interaction test and elevated plus maze to levels comparable to vehicle-treated animals.