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


Koester, Christina; Rudolph, Uwe; Haenggi, Tatjana; Papilloud, Aurélie; Fritschy, Jean-Marc; Crestani, Florence (2013). Dissecting the role of diazepam-sensitive γ-aminobutyric acid type A receptors in defensive behavioral reactivity to mild threat. Pharmacology Biochemistry and Behavior, 103(3):541-549.

Abstract

Moderate reductions in synaptic γ-aminobutyric acid(A) receptors (GABA(A)Rs) 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(A)Rs with point-mutated diazepam-insensitive either α1H101R or α3H126R-GABA(A)Rs, and double point-mutated α1H101Rα2H101R and α1H101Rα3H126R mice were used to uncover the GABA(A)R 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 (1.5mg/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-GABA(A)R function. These results reveal α2-containing GABA(A)Rs 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-GABA(A)Rs remains effective in reducing risk assessment, but not behavioral aversion.

Abstract

Moderate reductions in synaptic γ-aminobutyric acid(A) receptors (GABA(A)Rs) 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(A)Rs with point-mutated diazepam-insensitive either α1H101R or α3H126R-GABA(A)Rs, and double point-mutated α1H101Rα2H101R and α1H101Rα3H126R mice were used to uncover the GABA(A)R 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 (1.5mg/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-GABA(A)R function. These results reveal α2-containing GABA(A)Rs 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-GABA(A)Rs remains effective in reducing risk assessment, but not behavioral aversion.

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9 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:January 2013
Deposited On:21 Mar 2013 16:14
Last Modified:05 Apr 2016 16:32
Publisher:Elsevier
ISSN:0091-3057
Publisher DOI:https://doi.org/10.1016/j.pbb.2012.10.004
PubMed ID:23067879

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