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NEUROPHARMACOLOGY

An Inverse Agonist Selective for 5 Subunit-Containing GABA_A Receptors Enhances Cognition

Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (G.R.D., K.A.M., N.C., A.M.M., H.I.C., L.M.M., G.P., W.R., A.J.S., F.S., F.D.T., K.A.W., D.S.R., J.R.A.); Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom (M.C., B.J.E.); and Merck Research Laboratories, West Point, Pennsylvania (G.R.S.)

5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABA_A receptors containing an 1, 2, 3, or 5 subunit but has inverse agonist efficacy selective for the 5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABA_A receptors containing an 5 subunit. In a mouse hippocampal slice model, 5IA significantly enhanced the 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 5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, 5IA 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 5IA 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, 5IA 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 GABA_A 5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.

Address correspondence to: Dr. John R. Atack, Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Rd., Harlow, Essex CM20 2QR, UK. E-mail: john_atack{at}merck.com

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