The effects of ondansetron (GR38032F) in rats and mice treated subchronically with diazepam

Using rat and mouse models of aversive behaviour, we have further investigated the properties of the 5-HT3 receptor antagonist ondansetron (GR38032F) that are relevant to its proposed use as an anxiolytic agent. Tolerance to the disinhibitory properties of diazepam was readily demonstrated in the social interaction test in the rat, but did not occur after subchronic treatment with ondansetron. In both the light/dark exploration test in mice and the social interaction test in rats, withdrawal from subchronic treatment with diazepam increased behavioural suppression, whereas this was not observed with ondansetron. The behavioural suppression and weight loss induced by either the withdrawal of diazepam or the administration of the benzodiazepine receptor antagonist, flumazenil, in animals treated subchronically with diazepam, was prevented or antagonised by diazepam or ondansetron. Buspirone was ineffective. It is concluded that, in rats and mice, tolerance to the disinhibitory effects of ondansetron does not occur, that withdrawal from subchronic treatment with ondansetron is not associated with any behavioural disturbances and that ondansetron is highly effective in preventing the behavioural suppression and weight loss following withdrawal from subchronic diazepam treatment. These data suggest that ondansetron may have major therapeutic advantages over currently available anxiolytic agents, particularly in patients who have previously received prolonged benzodiazepine therapy.