Barbiturate-benzodiazepine interactions at the gamma-aminobutyric acidA receptor in rat cerebral cortical synaptoneurosomes.
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.
Department of Chemistry, University of Alabama, Birmingham.
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DeLorey
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Kissin
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Brown
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D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009118:Muscimol / Q000378:metabolism; D011868:Radioisotopes; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects
D001463:Barbiturates; D002712:Chlorides; D011868:Radioisotopes; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D009118:Muscimol