title: L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors.
abstract: The in vitro and in vivo properties of L-655,708, a compound with higher affinity for GABA(A) receptors containing an alpha5 compared to an alpha1, alpha2 or alpha3 subunit have been examined further. This compound has weak partial inverse agonist efficacy at each of the four subtypes but, and consistent with the binding data, has higher functional affinity for the alpha5 subtype. In a mouse hippocampal slice model, L-655,708 was able to enhance the long-term potentiation produced by a theta burst stimulation, consistent with a potential role for the alpha5 subtype in processes involving synaptic plasticity, such as learning and memory. When administered in a formulation specifically designed to achieve relatively constant plasma drug concentrations, and therefore maintain selective occupancy of alpha5- compared to alpha1-, alpha2- and alpha3-containing receptors (75+/-4% versus 22+/-10%, respectively), L-655,708 did not alter the dose of pentylenetetrazole required to induce seizures, indicating that the inverse agonist effects of L-655,708 at the alpha5 subtype are not associated with a proconvulsant liability. In the Morris water maze, L-655,708 enhanced performance not only during acquisition but also in a probe trial, demonstrating that this compound has cognition enhancing effects. These data further support the potential of alpha5-containing GABA(A) receptors as a target for novel cognition enhancing drugs.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. JAtack@prdus.jnj.com
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bayley
authors.forename: Guy R
authors.initials: GR
authors.lastname: Seabrook
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: Ruth M
authors.initials: RM
authors.lastname: McKernan
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003292:Convulsants / Q000494:pharmacology*; D004594:Electrophysiology; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics; D011994:Recombinant Proteins; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D003292:Convulsants; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; C496250:Gabra5 protein, mouse; D007093:Imidazoles; C105490:L 655,708; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D010433:Pentylenetetrazole