Resuscitative effect of a GABAB receptor antagonist on gamma-hydroxybutyric acid (GHB) mortality in mice.

Objective: In the present study a number of compounds were tested to evaluate their efficacy in exerting a protective effect on GHB-induced mortality in mice. The drugs investigated were: the GABAB receptor antagonist SCH 50911, the GABAA receptor antagonist bicuculline, the benzodiazepine receptor antagonist flumazenil, the putative ?-hydroxybutyric acid (GHB) receptor antagonist NCS-382, the opioid receptor antagonist naltrexone, and the amino acid and possible neuromodulator, taurine. Methods: All mice were initially treated with a lethal dose of GHB (7 g/kg, i.g.). Once mice had displayed clear signs of GHB intoxication, animals from each group were treated acutely with either SCH 50911 (vehicle, 75, 150, and 300 mg/kg, i.p.), bicuculline (vehicle, 2, 4, 6, and 8 mg/kg, i.p.), flumazenil (vehicle, 1, 3, and 10 mg/kg, i.p.), NCS-382 (vehicle, 50, and 200 mg/kg, i.p.), naltrexone (vehicle, 3, and 10 mg/kg, i.p.), or taurine (vehicle, 250, and 750 mg/kg, i.p.). The various doses of each single drug were administered to n=10 mice, randomly allocated throughout the experimental groups. Mortality was recorded every hour for the first 9 hours and subsequently 12, 18, and 24 hours after GHB injection. Results: In each experiment, all vehicle-treated mice died within 24 hours of GHB injection. Doses of 150 and 300 mg/kg SCH 50911 produced a marked protection on GHB-induced mortality, evidenced by the death of only 0/10 and 2/10 mice in the 150 and 300 mg/kg-SCH 50911 groups, respectively. In contrast, at all doses tested neither bicuculline, flumazenil, NCS-382, naltrexone or taurine were observed to exert any protective effect on GHB-induced mortality (9-10/10 mice died in each treatment group). Conclusion: These results suggest an involvement of the GABAB receptor, at least in rodents, in the mediation of the lethal effects of GHB.