RT Journal Article SR Electronic T1 An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1335 OP 1345 DO 10.1124/jpet.105.092320 VO 316 IS 3 A1 G. R. Dawson A1 K. A. Maubach A1 N. Collinson A1 M. Cobain A1 B. J. Everitt A1 A. M. MacLeod A1 H. I. Choudhury A1 L. M. McDonald A1 G. Pillai A1 W. Rycroft A1 A. J. Smith A1 F. Sternfeld A1 F. D. Tattersall A1 K. A. Wafford A1 D. S. Reynolds A1 G. R. Seabrook A1 J. R. Atack YR 2006 UL http://jpet.aspetjournals.org/content/316/3/1335.abstract AB α5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABAA receptors containing an α1, α2, α3, or α5 subunit but has inverse agonist efficacy selective for the α5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABAA receptors containing an α5 subunit. In a mouse hippocampal slice model, α5IA significantly enhanced the θ burst-induced long-term potentiation of the excitatory postsynaptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data suggesting that α5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, α5IA significantly enhanced performance in a rat hippocampal-dependent test of learning and memory, the delayed-matching-to-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice α5IA was not convulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, α5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABAA α5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.