Barbiturate-benzodiazepine Interactions at the Gamma-Aminobutyric acidA Receptor in Rat Cerebral Cortical Synaptoneurosomes

Anesth Analg. 1993 Sep;77(3):598-605. doi: 10.1213/00000539-199309000-00030.

Abstract

Combinations of benzodiazepines (midazolam and diazepam) with barbiturates (pentobarbital and phenobarbital) exhibit synergistic (supra-additive) hypnotic interactions in rats. Because both benzodiazepines and barbiturates interact with the gamma-aminobutyric acidA (GABAA) receptor complex, we have tested the hypothesis that these supra-additive hypnotic interactions are due to a synergistic effect on Cl- conductance subsequent to binding at allosterically coupled sites on the GABAA receptor ionophore complex. Equilibrium binding and 36Cl- flux measurements were performed under nearly identical conditions using rat brain cerebrocortical synaptoneurosomes. The benzodiazepines and barbiturates alone both allosterically enhance binding of [3H]muscimol to comparable, but modest, extents (range = 18%-32% enhancement). Isobolographic analysis reveals that combinations of benzodiazepines and barbiturates do in fact produce a synergistic enhancement of [3H]muscimol binding. Paradoxically, this effect is not translated into a synergistic enhancement of muscimol-stimulated 36Cl- flux. Because the positively cooperative interactions between benzodiazepines and barbiturates, as demonstrated both behaviorally and by binding measurements, are not reflected in enhanced Cl- conductance, the mechanistic basis for hypnotic synergism may involve other non-GABAergic components.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Barbiturates / pharmacology*
  • Benzodiazepines / pharmacology*
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / ultrastructure
  • Chlorides / metabolism
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Male
  • Muscimol / metabolism
  • Radioisotopes
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / drug effects*
  • Reflex / drug effects

Substances

  • Barbiturates
  • Chlorides
  • Radioisotopes
  • Receptors, GABA-A
  • Benzodiazepines
  • Muscimol