Dissecting the role of diazepam-sensitive γ-aminobutyric acid type A receptors in defensive behavioral reactivity to mild threat.
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.
Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Christina
C
Koester
Uwe
U
Rudolph
Tatjana
T
Haenggi
Aurélie
A
Papilloud
Jean-Marc
JM
Fritschy
Florence
F
Crestani
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005260:Female; D055879:Gene Knock-In Techniques; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D017354:Point Mutation / Q000235:genetics / Q000502:physiology; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D003975:Diazepam