Effect of benzodiazepine and β-carboline antagonists and partial agonists on loprazolam- and ZK 93423-induced hypothermia

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The pharmacology of the hypothermia induced by benzodiazepine and β-carboline full agonists in mice has been investigated using partial agonists and antagonists from both chemical series. The benzodiazepine antagonist flumazenil (10 mg/kg i.p.) blocked the hypothermia induced by loprazolam (3 mg/kg i.p.) but not that induced by the β-carboline ZK 93423 (3 mg/kg i.p.). Both hypothermic responses were reduced by the β-carboline antagonist ZK 93426 (3 mg/kg i.p.) and the benzodiazepine partial agonist Ro 17-1812 (10 mg/kg i.p.). On the other hand, the β-carboline partial agonist ZK 91296 (30 mg/kg i.p.) blocked ZK 93423-hypothermia but not that induced by loprazolam. Thus, the hypothermic actions of benzodiazepine and β-carboline agonists appear to be differentially antagonised by antagonists and partial agonists of the two chemical classes suggesting receptor subtype interactions which are non-uniformly related to the chemical class. These results cannot be explained simply in terms of pharmacokinetics or thermoregulatory effects of the compounds themselves. They suggest that, at least in the hypothalamus, different subtypes of benzodiazepine receptor may exist.