L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors.

Full 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.

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Author information

Author/s: Atack, John R (JR); Bayley, Peter J (PJ); Seabrook, Guy R (GR); Wafford, Keith A (KA); McKernan, Ruth M (RM); Dawson, Gerard R (GR);

Affiliation: Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. JAtack(-atsign-)prdus.jnj.com

Journal and publication information

Publication Type: In Vitro; Journal Article

Journal: Neuropharmacology (Neuropharmacology), published in England. (Language: eng)

Reference: 2006-Nov; vol 51 (issue 6) : pp 1023-9

Dates: Created 2006/11/06; Completed 2007/01/11;

PMID: 17046030, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Cognition - drug effects
Convulsants - pharmacology
Electrophysiology
GABA Agonists - administration & dosage; pharmacology
Hippocampus - drug effects
Humans
Imidazoles - administration & dosage; pharmacology
Long-Term Potentiation - drug effects
Male

Maze Learning
Memory - drug effects
Mice
Mice, Inbred C57BL
Patch-Clamp Techniques
Pentylenetetrazole - pharmacology
Rats
Receptors, GABA-A - agonists; genetics
Recombinant Proteins
Seizures - chemically induced; physiopathology

Associated Chemicals: Convulsants (0) ; GABA Agonists (0) ; Gabra5 protein, mouse (0) ; Imidazoles (0) ; L 655,708 (0) ; Receptors, GABA-A (0) ; Recombinant Proteins (0) ; Pentylenetetrazole (54-95-5)

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