Differential effects of the benzodiazepine antagonist Ro 15-1788 after "general anaesthetic" doses of benzodiazepines in mice.

The effects of the benzodiazepine antagonist Ro 15-1788 20 mg kg-1 after "general anaesthetic" doses of several benzodiazepines were studied in mice, in order to determine if the effects of the latter were attributable to an action at benzodiazepine receptors. Male CDI mice were used and the end-points for anaesthesia were loss of the righting reflex and loss of the foot pinch reflex. The effects of midazolam, and to a lesser extent those of chlordiazepoxide and of diazepam on these reflexes, were antagonized partially by Ro 15-1788. When the antagonist was given after high doses of flurazepam, convulsions were produced. Calculation of the likely membrane concentrations of the benzodiazepines showed that these fitted the lipid solubility correlation for general anaesthesia. Ro 15-1788 did not decrease the lethal effects of the benzodiazepines. With flurazepam, chlordiazepoxide and diazepam it caused signs of hyperexcitability, which in the case of flurazepam led to the death of the animals.