Effects of the 5-HT3 antagonist GR38032F (ondansetron) on benzodiazepine withdrawal in rats.

Effects of the 5-HT3 receptor antagonist GR38032F (ondansetron) on chlordiazepoxide withdrawal were assessed in rats which received chlordiazepoxide b.i.d. for 21 days at doses up to 40 mg/kg per injection. Withdrawal signs recorded were: body weight and food intake, which fell and then recovered over 9 days. Saline or GR38032F (1.0, 0.1 or 0.01 mg/kg) were administered b.i.d. during withdrawal. Clear withdrawal signs were seen in rats treated with saline after chronic chlordiazepoxide. However, GR38032F at 0.1 mg/kg reduced the severity of withdrawal. At 0.01 mg/kg GR38032F shortened withdrawal duration, but did not diminish peak withdrawal signs. At 1.0 mg/kg GR38032F, did not attenuate withdrawal signs at all. GR38032F (0.01-1.0 mg/kg) had no effect on ad lib food intake, therefore the attenuation of withdrawal was probably not simply due to stimulation of appetite. These data support recent claims that GR38032F attenuates benzodiazepine withdrawal, and they indicate that this effect shows an inverted U-shaped dose-response curve.