A Pharmacogenetic 'Restriction-of-Function' Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by alpha 5-Containing GABA(A) Receptors in Mice

作者：Behlke, Lauren M.; Foster, Rachel A.; Liu, Jing; Benke, Dietmar; Benham, Rebecca S.; Nathanson, Anna J.; Yee, Benjamin K.; Zeilhofer, Hanns Ulrich; Engin, Elif; Rudolph, Uwe^*

来源：Neuropsychopharmacology, 2016, 41(10): 2492-2501.

DOI：10.1038/npp.2016.49

• ELEVATED PLUS-MAZE
• ALLOSTERIC MODULATOR
• BENZODIAZEPINES
• SUBTYPES
• ALPHA-3
• ANXIETY
• SB-205384
• SUBUNITS
• REWARD
• FEAR

Benzodiazepines have been widely used for their anxiolytic actions. However, the contribution of GABA(A) receptor subtypes to anxiolysis is still controversial. Studies with mutant mice harboring diazepam-insensitive alpha-subunits alpha 1, alpha 2, alpha 3, or alpha 5 have revealed that alpha 2-containing GABA(A) receptors (alpha 2-GABA(A)Rs) are required for diazepam-induced anxiolysis, with no evidence for an involvement of any other a-subunit, whereas TP003, described as a selective modulator of alpha 3-containing GABA(A) 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 a-subtypes in anxiety-related behavioral paradigms. By combining H to R point mutations in three out of the four diazepam-sensitive a-subunits in mice with a 129X1/SvJ background, diazepam becomes a subtype-specific modulator of the remaining non-mutated a-subtype. Modulation of alpha 5-GABA(A)Rs, but not of alpha 2-GABA(A)Rs, 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 alpha 3-GABA(A)Rs decreased open-arm exploration, whereas modulation of a2-GABA(A)Rs increased time in the center in the open-field test. Modulation of any single a-subtype had no effect on stress-induced hyperthermia. Our results provide evidence that modulation of alpha 5-GABA(A)Rs elicits anxiolytic-like actions, whereas our data do not provide evidence for an anxiolytic-like action of alpha 3-GABAARs. Thus, alpha 5-GABA(A)Rs may be suitable targets for novel anxiolytic drugs.

• 出版日期2016-9
• 单位香港理工大学