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

摘要

Moderate reductions in synaptic ??-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 ??2 subunit-containing GABAergic synapses is sufficient to cause this anxiety-related phenotype and to prevent its attenuation by the benzodiazepine. Wild type (??2 +/+), heterozygous (??2 +/-) and homozygous (??2 -/-) knock-out littermates were tested in the free-choice exploratory (FCE) and the light/dark choice (LDC) paradigms. ??2 -/- mice, double mutant ??1H101R??2 -/- and ??3H126R??2 -/- mice, which combine a lack of ??2-GABA ARs with point-mutated diazepam-insensitive either ??1H101R or ??3H126R-GABAARs, and double point-mutated ??1H101R?? 2H101R and ??1H101R??3H126R mice were used to uncover the GABA AR subtype(s) mediating the drug effects. Data show that in the FCE, ??2 -/- 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 ??2 +/- and ??2 +/+ mice. In the LDC, ??2 -/- 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 ??2 +/- and ??2 +/+ mice in the two paradigms. Diazepam (1.5 mg/kg per os) normalized retractions and latencies in the FCE in ??2 -/- and ??3H126R??2 -/- mice, but not in ??1H101R??2 -/- mice. The same drug treatment failed to attenuate behavioral aversion in both paradigms in all mutants with impaired ??2-GABAAR function. These results reveal ??2-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 ??1-GABAARs remains effective in reducing risk assessment, but not behavioral aversion. ? 2012 Elsevier Inc. All rights reserved.