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Title: A pharmacogenetic ‘Restriction-of-function’ approach reveals evidence for anxiolytic-like actions mediated by α5-containing GABAA receptors in mice
Other Titles: A pharmacogenetic ‘Restriction-of-function’ approach reveals evidence for anxiolytic-like actions mediated by α5-containing GABA[sub A] receptors in mice
Authors: Behlke, LM
Foster, RA
Liu, J
Benke, D
Benham, RS
Nathanson, AJ
Yee, BK 
Zeilhofer, HU
Engin, E
Rudolph, U
Issue Date: Sep-2016
Publisher: Springer Nature
Source: Neuropsychopharmacology, Sept. 2016, v. 41, p. 2492-2501 How to cite?
Journal: Neuropsychopharmacology 
Abstract: Benzodiazepines have been widely used for their anxiolytic actions. However, the contribution of GABAA receptor subtypes to anxiolysis is still controversial. Studies with mutant mice harboring diazepam-insensitive α-subunits α1, α2, α3, or α5 have revealed that α2-containing GABAA receptors (α2-GABAARs) are required for diazepam-induced anxiolysis, with no evidence for an involvement of any other α-subunit, whereas TP003, described as a selective modulator of α3-containing GABAA receptors, was shown to be anxiolytic. Here, we describe a novel, systematic approach to evaluate the role of positive allosteric modulation of each of the four diazepam-sensitive α-subtypes in anxiety-related behavioral paradigms. By combining H to R point mutations in three out of the four diazepam-sensitive α-subunits in mice with a 129X1/SvJ background, diazepam becomes a subtype-specific modulator of the remaining non-mutated α-subtype. Modulation of α5-GABAARs, but not of α2-GABAARs, increased the time in the light side of the light–dark box as well as open-arm exploration in the elevated plus maze. In contrast, modulation of α3-GABAARs decreased open-arm exploration, whereas modulation of α2-GABAARs increased time in the center in the open-field test. Modulation of any single α-subtype had no effect on stress-induced hyperthermia. Our results provide evidence that modulation of α5-GABAARs elicits anxiolytic-like actions, whereas our data do not provide evidence for an anxiolytic-like action of α3-GABAARs. Thus, α5-GABAARs may be suitable targets for novel anxiolytic drugs.
ISSN: 0893-133X
EISSN: 1740-634X
DOI: 10.1038/npp.2016.49
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