Non-selective
benzodiazepines, such as
diazepam, interact with equivalent affinity and agonist efficacy at
GABA(A) receptors containing either an alpha1, alpha2, alpha3 or alpha5 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 (alpha1H101R, alpha2H101R or alpha5H105R) or multiple (alpha125H-->R) alpha subunits that render the resulting
GABA(A) receptors diazepam-insensitive. Furthermore, the
anticonvulsant properties of
diazepam, the alpha1- and alpha3-selective compounds
zolpidem and
TP003, respectively, and the alpha2/alpha3 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 alpha3 nor alpha5 subtypes appeared to confer
anticonvulsant activity. Moreover, whereas the alpha1 and alpha2 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 alpha2-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.