Electrophysiological and pharmacological actions of the convulsant benzodiazepine Ro 5-4864.
Ro 5-4864 (4'-chlorodiazepam) elicited convulsions in mice with a CD50 of 23.5 mg/kg (i.p.) and increased the firing rate of substantia nigra zona reticulata neurons in a dose dependent fashion (0.5-4 mg/kg i.v.). Diazepam and clonazepam, but not Ro 15-1788, were potent inhibitors of Ro 5-4864 induced convulsions. Ro 15-1788 was also ineffective in reversing Ro 5-4864 induced increases in cell firing of zone reticulata neurons. Muscimol potently inhibited the seizures and reversed increases in cell firing elicited by Ro 5-4864. Phenobarbital and pentobarbital inhibited Ro 5-4864 induced convulsions with moderate potencies, while phenytoin and carbamazepine were ineffective at doses of up to 100 mg/kg. These observations suggest that Ro 5-4864 does not elicit its pharmacologic actions through a direct action at a 'brain-type' benzodiazepine receptor. However, both the profile and potency of compounds effective in inhibiting the electrophysiological and pharmacological effects of Ro 5-4864 suggest that this compound may act by perturbation of a component of the GABA-benzodiazepine receptor chloride ionophore complex. These findings do not, however, rule out a direct involvement of the high affinity 'peripheral-type' benzodiazepine receptors found in brain.
D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001921:Brain / Q000502:physiology; D003292:Convulsants / Q000378:metabolism / Q000494:pharmacology*; D004594:Electrophysiology; D008297:Male; D009118:Muscimol / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000502:physiology*; D011963:Receptors, GABA-A; D012640:Seizures / Q000517:prevention & control*; D013378:Substantia Nigra / Q000502:physiology*
D001570:Benzodiazepinones; D003292:Convulsants; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D009118:Muscimol; C028513:4'-chlorodiazepam