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Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic ef

Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic ef

  1. Jatelka
    J Neurosci. (javascript:AL_get(this, 'jour', 'J Neurosci.');) 2005 Nov 16;25(46):10682-8.

    Dias, Rebecca ; Sheppard, Wayne F A ; Fradley, Rosa L ; Garrett, Elizabeth M ; Stanley, Joanna L ; Tye, Spencer J ; Goodacre, Simon ; Lincoln, Rachael J ; Cook, Susan M ; Conley, Rachel ; Hallett, David ; Humphries, Alexander C ; Thompson, Sally A ; Wafford, Keith A ; Street, Leslie J ; Castro, J Luis ; Whiting, Paul J ; Rosahl, Thomas W ; Atack, John R ; Mckernan, Ruth M ; Dawson, Gerard R ; Reynolds, David S

    The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-รก]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.