Benzodiazepine agonist and inverse agonist actions on GABA(A) receptor-operated chloride channels. I. Acute effects of ethanol

K. J. Buck, R. A. Harris

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Acute exposure to ethanol was found to enhance the ability of a benzodiazepine (BZ) inverse agonist, methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), to reduce muscimol-activated 36Cl- uptake by membranes isolated from mouse cerebral cortex. Pretreatment in vivo with a hypnotic dose of ethanol (but not a subhypnotic dose), or exposure to a corresponding concentration in vitro, was effective. This increase in sensitivity of γ-aminobutyric acid receptor-operated chloride channels to the actions of DMCM was due to an increase in both the potency and efficacy of DMCM. Sensitization to DMCM was reversible and was not observed 24 hr after a single injection of ethanol. Pretreatment with ethanol (10, 50 and 100 mM) in vitro produced sensitization to DMCM in a concentration-dependent manner, similar to that produced by in vivo exposure; this increase in sensitivity did not develop if the membranes were pretreated with ethanol at 0°C. Similarly, in vitro exposure to pentobarbital (200 μM) or flunitrazepam (1 μM) enhanced the actions of the inverse agonist Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]BZ-3- carboxylate). Acute ethanol exposure did not alter low-affinity γ-aminobutyric acid(A) receptor binding or muscimol action, or the ability of a BZ agonist, flunitrazepam, to augment muscimol-activated chloride flux. Ethanol exposure did not alter [3H]flumazenil (Ro-15-1788) binding to central BZ receptors, its displacement by DMCM or allosteric modulation of DMCM binding by muscimol (muscimol-shift). These results suggest that exposure to ethanol increases coupling between BZ inverse agonist sites and the chloride channel without altering the coupling BZ agonist sites. This action may be involved in antagonism of ethanol intoxication by BZ inverse agonists. Furthermore, sensitization to the actions of endogenous inverse agonists may play a role in the development of acute tolerance to ethanol, BZs and barbiturates.

Original languageEnglish (US)
Pages (from-to)706-712
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1990
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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