Dissecting the role of diazepam-sensitive γ-aminobutyric acid type A receptors in defensive behavioral reactivity to mild threat

Christina Koester, Uwe Rudolph, Tatjana Haenggi, Aurélie Papilloud, Jean Marc Fritschy, Florence Crestani

Research output: Contribution to journalArticlepeer-review

Abstract

Moderate reductions in synaptic γ-aminobutyric acidA receptors (GABAARs) have been associated with an enhanced defensive behavioral reactivity to mild threat, sensitive to diazepam. We here tested whether a deficit in α2 subunit-containing GABAergic synapses is sufficient to cause this anxiety-related phenotype and to prevent its attenuation by the benzodiazepine. Wild type (α2 +/+), heterozygous (α2 +/-) and homozygous (α2 -/-) knock-out littermates were tested in the free-choice exploratory (FCE) and the light/dark choice (LDC) paradigms. α2 -/- mice, double mutant α1H101Rα2 -/- and α3H126Rα2 -/- mice, which combine a lack of α2-GABA ARs with point-mutated diazepam-insensitive either α1H101R or α3H126R-GABAARs, and double point-mutated α1H101Rα 2H101R and α1H101Rα3H126R mice were used to uncover the GABA AR subtype(s) mediating the drug effects. Data show that in the FCE, α2 -/- mice exhibited more retractions (i.e. risk assessment) and longer latencies to first occurrence into the novel compartment and less transitions and time spent inside it in comparison to α2 +/- and α2 +/+ mice. In the LDC, α2 -/- mice visited and spent less time in the lit box and stayed longer in the tunnel than the other two groups. Minor differences were found between α2 +/- and α2 +/+ mice in the two paradigms. Diazepam (1.5 mg/kg per os) normalized retractions and latencies in the FCE in α2 -/- and α3H126Rα2 -/- mice, but not in α1H101Rα2 -/- mice. The same drug treatment failed to attenuate behavioral aversion in both paradigms in all mutants with impaired α2-GABAAR function. These results reveal α2-containing GABAARs as key molecular determinants in the regulation of anxiety-related responses elicited by exposure to relative novelty and mild threat. In the absence of these receptors, diazepam through activation of α1-GABAARs remains effective in reducing risk assessment, but not behavioral aversion.

Original languageEnglish (US)
Pages (from-to)541-549
Number of pages9
JournalPharmacology Biochemistry and Behavior
Volume103
Issue number3
DOIs
StatePublished - Jan 2013
Externally publishedYes

Keywords

  • Anxiety
  • Diazepam
  • Gabra2
  • Mutant mice
  • γ-Aminobutyric acid type A receptor

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

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