Antagonism of hypothermia produced by benzodiazepine-related compounds by U-78875 in mice

The benzodiazepine receptor agonists, flurazepam, zolpidem, ZK 93423, and the benzodiazepine inverse agonist, FG 7142, all produced hypothermia when injected i.p. in mice. These compounds are structurally different and do not have the same affinity for the GABAA/benzodiazepine receptor subtypes. Pretreatment with flumazenil (30 mg/kg) completely blocked the hypothermia produced by flurazepam (30 mg/kg), zolpidem (3 mg/kg), and FG 7142 (60 mg/kg), only partially reversed ZK 93423 (3 mg/kg), and was ineffective against 10 mg/kg zolpidem. In comparison, 3 mg/kg of U-78875 completely antagonized all these benzodiazepine agonists. When injected before 30 mg/kg pentobarbital, U-78875 (3 mg/kg) slightly enhanced and prolonged the hypothermic effect of pentobarbital, while flumazenil had very little effect. The results show that U-78875 is a potent antagonist against benzodiazepine receptor agonists, while having demonstrable intrinsic activity.