Evidence for a Significant Role of α3-Containing GABAAReceptors in Mediating the Anxiolytic Effects of Benzodiazepines

• DOI: 10.1523/jneurosci.1166-05.2005
• Publication Date: 2005-11-16T21:38:03Z
• Authors: 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. Hump...; 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; David S. Reynolds
• Keywords: Male; Dose-Response Relationship, Drug; Mice, Transgenic; Anxiety; Receptors, GABA-A; Rats; 3. Good health; Rats, Sprague-Dawley; Benzodiazepines; Mice; Protein Subunits; 03 medical and health sciences; 0302 clinical medicine; Anti-Anxiety Agents; Animals; Humans; GABA-A Receptor Agonists; Saimiri; Protein Binding

The GABAAreceptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that α2-rather than α3-containing GABAAreceptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an α3-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 α3 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 α2-containing receptors BZ insensitive (α2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of α3-containing GABAAreceptors is sufficient to produce the anxiolytic effects of BZs and that α2 potentiation may not be necessary.