An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition

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Abstract
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.

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