Electrophysiological and pharmacological actions of the convulsant benzodiazepine Ro 5-4864

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Abstract

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 reticula 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 reticula 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.

References (34)

  • B.A. Weissman et al.

    Ro 5-4864: A potent benzodiazepine convulsant

    European J. Pharmacol.

    (1983)
  • G. Zbinden et al.

    Pharmacology of benzodiazepines: Laboratory and clinical correlations

    Adv. Pharmacol.

    (1967)
  • P. Albright et al.

    Development of a new pharmacological seizure model: Effects of anticonvulsants on cortical- and amygdala-kindled seizures in rats

    Epilepsia

    (1980)
  • D. Ashtan et al.

    Behavioral analysis of the effects of 15 anticonvulsants in the amygdaloid kindled rat

    Psychopharmacology

    (1979)
  • A. Bowling et al.

    Micromolar affinity benzodiazepine receptors: Identification and characterization in central nervous system

    Science

    (1982)
  • C. Braestrup et al.

    Specific benzodiazepine receptors in rat brain characterized by high affinity [3H]diazepam binding

  • B.S. Bunney et al.

    Dopaminergic neurons: Effects of antipsychotic drugs and amphetamine on single cell activity

    J. Pharmacol. Exp. Ther.

    (1973)
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