Requirement of α5-GABAA receptors for the development of tolerance to the sedative action of diazepam in mice

Carolien Van Rijnsoever, Marcus Täuber, Mohamed Khaled Choulli, Ruth Keist, Uwe Rudolph, Hanns Mohler, Jean Marc Fritschy, Florence Crestani

Research output: Contribution to journalArticlepeer-review

Abstract

Despite its pharmacological relevance, the mechanism of the development of tolerance to the action of benzodiazepines is essentially unknown. The acute sedative action of diazepam is mediated via α1-GABAA receptors. Therefore, we tested whether chronic activation of these receptors by diazepam is sufficient to induce tolerance to its sedative action. Knock-in mice, in which the α1-, α2-, α3-, or α5-GABAA receptors had been rendered insensitive to diazepam by histidine-arginine point mutation, were chronically treated with diazepam (8 d; 15 mg · kg-1 · d-1) and tested for motor activity. Wild-type, α 2(H101R), and α3(H126R) mice showed a robust diminution of the motor-depressant drug action. In contrast, α5(H105R) mice failed to display any sedative tolerance. α1(H101R) mice showed no alteration of motor activity with chronic diazepam treatment. Autoradiography with [3H]flumazenil revealed no change in benzodiazepine binding sites. However, a decrease in α5-subunit radioligand binding was detected selectively in the dentate gyrus with specific ligands. This alteration was observed only in diazepam-tolerant animals, indicating that the manifestation of tolerance to the sedative action of diazepam is associated with a downregulation of α5-GABAA receptors in the dentate gyrus. Thus, the chronic activation of α5-GABAA receptors is crucial for the normal development of sedative tolerance to diazepam, which manifests itself in conjunction with α1-GABAA receptors.

Original languageEnglish (US)
Pages (from-to)6785-6790
Number of pages6
JournalJournal of Neuroscience
Volume24
Issue number30
DOIs
StatePublished - Jul 28 2004
Externally publishedYes

Keywords

  • Dentate gyrus
  • Diazepam
  • GABA receptor
  • Knock-in mice
  • Motor activity
  • Tolerance

ASJC Scopus subject areas

  • Neuroscience(all)

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