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The Journal of Neuroscience, November 16, 2005, 25(46):10682-10688; doi:10.1523/JNEUROSCI.1166-05.2005

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Behavioral/Systems/Cognitive
Evidence for a Significant Role of 3-Containing GABA_A Receptors in Mediating the Anxiolytic Effects of Benzodiazepines

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

The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom

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 2-rather than 3-containing GABA_A receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an 3-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-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an 3 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 2-containing receptors BZ insensitive (2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of 3-containing GABA_A receptors is sufficient to produce the anxiolytic effects of BZs and that 2 potentiation may not be necessary.

Key words: GABA_A; benzodiazepine; anxiety; 3 subunit; agonist; stress-induced hyperthermia

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Received March 24, 2005; revised October 3, 2005; accepted October 4, 2005.

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