| First Author | Koester C | Year | 2013 |
| Journal | Pharmacol Biochem Behav | Volume | 103 |
| Issue | 3 | Pages | 541-9 |
| PubMed ID | 23067879 | Mgi Jnum | J:234232 |
| Mgi Id | MGI:5789544 | Doi | 10.1016/j.pbb.2012.10.004 |
| Citation | Koester C, et al. (2013) Dissecting the role of diazepam-sensitive gamma-aminobutyric acid type A receptors in defensive behavioral reactivity to mild threat. Pharmacol Biochem Behav 103(3):541-9 |
| abstractText | Moderate reductions in synaptic gamma-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 alpha2 subunit-containing GABAergic synapses is sufficient to cause this anxiety-related phenotype and to prevent its attenuation by the benzodiazepine. Wild type (alpha2+/+), heterozygous (alpha2+/-) and homozygous (alpha2-/-) knock-out littermates were tested in the free-choice exploratory (FCE) and the light/dark choice (LDC) paradigms. alpha2-/- mice, double mutant alpha1H101Ralpha2-/- and alpha3H126Ralpha2-/- mice, which combine a lack of alpha2-GABA(A)Rs with point-mutated diazepam-insensitive either alpha1H101R or alpha3H126R-GABA(A)Rs, and double point-mutated alpha1H101Ralpha2H101R and alpha1H101Ralpha3H126R mice were used to uncover the GABA(A)R subtype(s) mediating the drug effects. Data show that in the FCE, alpha2-/- 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 alpha2+/- and alpha2+/+ mice. In the LDC, alpha2-/- 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 alpha2+/- and alpha2+/+ mice in the two paradigms. Diazepam (1.5mg/kg per os) normalized retractions and latencies in the FCE in alpha2-/- and alpha3H126Ralpha2-/- mice, but not in alpha1H101Ralpha2-/- mice. The same drug treatment failed to attenuate behavioral aversion in both paradigms in all mutants with impaired alpha2-GABA(A)R function. These results reveal alpha2-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 alpha1-GABA(A)Rs remains effective in reducing risk assessment, but not behavioral aversion. |
