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Differential contribution of GABA_A receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

Martin R. Guscott

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

Sharlene Bull

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

David J. Hallett

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

Simon C. Goodacre

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

Keith A. Wafford

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

ELizabeth M. Garrett

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

Richard J. Newman

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

Gillian F. O'Meara

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

Paul J. Whiting

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

Thomas W. Rosahl

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

Gerard R. Dawson

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

David S. Reynolds

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK

John R. Atack

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK, JAtack{at}prdus.jnj.com

Non-selective benzodiazepines, such as diazepam, interact with equivalent affinity and agonist efficacy at GABA_A receptors containing either an 1, 2, 3 or 5 subunit. However, which of these particular subtypes are responsible for the anticonvulsant effects of diazepam remains uncertain. In the present study, we examined the ability of diazepam to reduce pentylenetetrazoLe (PTZ)-induced and maximal electroshock (MES)-induced seizures in mice containing point mutations in single (1H101R, 2H101R or 5H105R) or multiple (125HR) subunits that render the resulting GABA_A receptors diazepam-insensitive. Furthermore, the anticonvulsant properties of diazepam, the 1- and 3-selective compounds zoLpidem and TP003, respectively, and the 2/3 preferring compound TP13 were studied against PTZ-induced seizures. In the transgenic mice, no single subtype was responsible for the anticonvulsant effects of diazepam in either the PTZ or MES assay and neither the 3 nor 5 subtypes appeared to confer anticonvulsant activity. Moreover, whereas the 1 and 2 subtypes played a modest role with respect to the PTZ assay, they had a negligible role in the MES assay. With respect to subtype-selective compounds, zolpidem and TP003 had much reduced anticonvulsant efficacy relative to diazepam in both the PTZ and MES assays whereas TP13 had high anticonvulsant efficacy in the PTZ but not the MES assay. Taken together, these data not only indicate a role for 2-containing GABA_A receptors in mediating PTZ and MES anticonvulsant activity but also suggest that efficacy at more than one subtype is required and that these subtypes act synergistically.

Key Words: pentylenetetrazole • maximal electroshock • mouse • knock-in mice • GABAA • epilepsy • benzodiazepines

This version was published on June 1, 2007

Journal of Psychopharmacology, Vol. 21, No. 4, 384-391 (2007)
DOI: 10.1177/0269881106067255


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