α2-γ-Aminobutyric acid (GABA)A receptors are the molecular substrates mediating precipitation of narcosis but not of sedation by the combined use of diazepam and alcohol in vivo

Marcus Täuber, Elisabeth Calame-Droz, Laetitia Prut, Uwe Rudolph, Florence Crestani

Research output: Contribution to journalArticlepeer-review

Abstract

Classical benzodiazepines such as diazepam are widely used tranquillisers and hypnotics in various neuropsychiatric diseases including alcohol-related disorders. One of the major drawbacks of benzodiazepine therapy, however, is an exacerbation of the sedative and hypnotic effects associated with alcohol intake, even at low doses. Even though the γ-aminobutyric acid (GABA) A receptor complex is a common target for the actions of both classes of drugs, the molecular mechanisms underlying the enhanced pharmacological properties of the combined use of benzodiazepines and alcohol remain to be identified. The present experiments aimed at clarifying which of the GABAA receptor subtypes mediate the augmented hypnotic-like and sedative effects of combined diazepam and alcohol using the righting reflex and motor activity assays, respectively, in histidine-to-arginine point mutated mice that possess diazepam-insensitive α1-, α2-, α3- or α5-GABAA receptors. The combination of diazepam (2 or 3mg/kg) and ethanol (3g/kg) induced loss of righting reflex with a significantly dose-dependent increase of the latency to its full recovery in wild-type, α1 (H101R), α3(H126R) and α5(H105R) but not in α2(H101R) mice. A combined treatment with diazepam (1 mg/kg) and ethanol (2.5 g/kg) precipitated motor inhibition similarly in wild-type and α2(H101R) mice. Responsiveness of the α2(H101R) mice to ethanol alone was similar to that of wild-type mice. These results demonstrate that induction of loss of righting reflex by combined diazepam and alcohol is closely dependent on the activation of the α2-GABAA receptors by the benzodiazepine whereas precipitation of sedation involves GABAA receptors other than the α2-GABAA receptors.

Original languageEnglish (US)
Pages (from-to)2599-2604
Number of pages6
JournalEuropean Journal of Neuroscience
Volume18
Issue number9
DOIs
StatePublished - Nov 2003
Externally publishedYes

Keywords

  • Alcohol
  • Diazepam
  • GABA receptor
  • Histidine-to-arginine point mutated mice

ASJC Scopus subject areas

  • Neuroscience(all)

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