Abstracts

Since anticonvulsant drugs, including diazepam, quickly loose their efficacy after induction of status epilepticus in rats, the post Status Epilepticus (post-SE) model may be a useful model to study mechanisms underlying pharmacoresistance development. One of the causes of loss in efficacy may be alteration in subunit composition of the GABA[sub]A[/sub] receptor. In the present study the functionality of the GABA[sub]A[/sub]-receptor was studied [italic]in vivo[/italic] in the post-SE model, in which the SE was induced by [italic]ip[/italic] injections of kainic acid. Drugs enhancing GABAergic inhibition, which exhibit preference for certain receptor subtypes, were used: midazolam (MDZ, [alpha][sub]1,2,3,5[/sub],[gamma][sub]2[/sub]-enhancing), Zolpidem (ZPD, [alpha][sub]1,[/sub][gamma][sub]2[/sub]-enhancing), alphaxalone (ALP, [delta]-enhancing), and tiagabine (TGB, GABA-reuptake inhibitor, tonic inhibition- [alpha][sub]6[/sub], [delta]-enhancing). An experiment with an [italic]iv[/italic] administered GABAergic ligand (MDZ, n=8; ZPD, n=4; ALP, n=6; TGB, n=6) was performed in rats before and at 14 days after induction of SE. The power of the [beta]-frequency of the cortical EEG was used as measure for the enhancement of GABAergic inhibition. Arterial blood samples were collected simultaneously for pharmacokinetic analysis. As a first approximation the results were analysed using the Pharmacokinetic-Pharmacodynamic (PK-PD) model reported by Visser et al (JPET [2002] 302:1158-1167), which allows both the characterization of the sigmoid concentration-effect relation of MDZ, ZPD and TGB, and of the biphasic relationship of ALP with a single model. In this model the receptor activation process and the subsequent translation into response are characterized separately. If only changes in subunit composition would underly changes in functionality of the GABA[sub]A[/sub]-receptor, this would exclusively be reflected in alterations in the [italic]in vivo[/italic] intrinsic efficacy. Analysis of the data indicated a significant [italic]de[/italic]crease in effect of MDZ and ZPD after induction of SE (to 39% and 87% of control respectively), whereas the effect of ALP was significantly [italic]in[/italic]creased (up to 129%). This is consistent with a downregulation of [gamma][sub]2[/sub]-subunit- and an upregulation of [delta]-subunit-containing receptors. On the other hand the effect of TGB was not changed significantly. Furthermore, the PK-PD modelling and analysis of the EEG of ALP and TGB 14 days after induction of SE indicated that more complex changes occur than can be explained by a change in subunit composition of the GABA[sub]A[/sub] receptor alone. In conclusion, this study clearly shows that the [italic]in vivo[/italic] efficacy of the different ligands is altered by epilepsy. However, more studies with additional subunit-selective ligands are required to elucidate the precise mechanisms. (Supported by Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie and the National Epilepsy Fund.)