A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, beta-carbolines, and phenobarbitone

Naunyn Schmiedebergs Arch Pharmacol. 1982 Dec;321(4):260-4. doi: 10.1007/BF00498510.


The potent benzodiazepine receptor ligands beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) and the corresponding methylester (beta-CCM) administered i.v. depressed segmental dorsal root potentials in spinal cats, reversed the prolongation of dorsal root potentials by phenobarbitone, and abolished the depression of a motor performance task induced by phenobarbitone in mice; beta-CCE enhanced the low-frequency facilitation of pyramidal population spikes in the hippocampus of anaesthetized rats. These effects of beta-carbolines reflect a depression of GABAergic synaptic transmission and, thus, are diametrically opposed to the enhancing action of benzodiazepine tranquilizers. The specific benzodiazepine antagonist, Ro 15-1788, while not affecting dorsal root potentials, hippocampal population spikes or phenobarbitone-induced motor performance depression, abolished the effects of beta-CCE on the three parameters and similar effects of beta-CCM on the spinal cord and motor performance. A three-state model of the benzodiazepine receptor is proposed in which benzodiazepine tranquilizers act as agonists enhancing the function of the benzodiazepine receptor as a coupling unit between GABA receptor and chloride channel, beta-carbolines act as "inverse agonists" reducing this coupling function, and Ro 15-1788 represents a competitive antagonist blocking both the enhancing effect of agonists and the depressant effect of "inverse agonists" on GABAergic synaptic transmission.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Benzodiazepines / antagonists & inhibitors*
  • Benzodiazepinones / pharmacology*
  • Carbolines / pharmacology*
  • Cats
  • Female
  • Flumazenil
  • Hippocampus / drug effects
  • In Vitro Techniques
  • Indoles / pharmacology*
  • Male
  • Mice
  • Models, Biological*
  • Phenobarbital / pharmacology*
  • Rats
  • Receptors, Cell Surface / drug effects*
  • Receptors, GABA-A
  • Spinal Cord / drug effects


  • Anti-Anxiety Agents
  • Benzodiazepinones
  • Carbolines
  • Indoles
  • Receptors, Cell Surface
  • Receptors, GABA-A
  • Benzodiazepines
  • Flumazenil
  • beta-carboline-3-carboxylic acid ethyl ester
  • beta-carboline-3-carboxylic acid methyl ester
  • Phenobarbital