Differential contribution of GABAA receptor subtypes to the
anticonvulsant efficacy of benzodiazepine site ligands
Rose Fradley,
Martin Guscott,
Sharlene Bull,
David J Hallett,
Simon C. Goodacre,
Keith A. Wafford,
Elizabeth M. Garrett,
Richard Newman,
Gillian F. O'Meara,
Paul J. Whiting,
Thomas W. Roshal,
Gerard R. Dawson,
David S. Reynolds,
John Atack
Merck, Sharp and Dohme Research Laboratories, Neuroscience Research
Centre, Harlow, Essex, UK.
* To whom correspondence should be addressed.
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Abstract |
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Non-selective benzodiazepines, such as diazepam, interact with equivalent affinity
and agonist efficacy at GABAA 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 (125H
R) subunits that
render the resulting GABAA 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 GABAA 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
