The muscarinic agonist, pilocarpine, induces electrographic and behavioural signs of limbic seizures when administered locally in the hippocampus, an effect that is partly mediated by overactivity of glutamatergic synapses and which models temporal lobe epilepsy (Smolders et al. 1997). It is also well established that kainic acid produces several characteristics of this form of epilepsy (Nadler et al. 1978). Synaptic activation of the GLUK5 subtype of kainate receptor appears to be frequency dependent (Vignes et al. 1997). Therefore we tested the effect of the GLUK5 receptor antagonists, LY377770 and LY382884 (Lodge & Bleakman, 1998), on pilocarpine-induced seizure-related activities within the rat hippocampus.

Experiments, including humane killing, were conducted according to National Guidelines and approved by the VUB Ethics Committee for Animal Experimentation. Male Wistar rats (270-300 g) were anaesthetised with ketamine:diazepam (25:5 mg kg^-1 I.P.) to implant micro-dialysis probes into the hippocampus and to position an array of six dural EEG electrodes with dental cement. The rats were given 4 mg kg^-1 I.P. ketoprofen for post-operative analgesia and allowed to recover. Next day, the dialysis perfusion fluid was replaced with one containing 10 mM pilocarpine for 40 min. This invariably (n = 8) resulted in scratching, wet dog shakes and tonic-clonic seizures. The behavioural signs were accompanied by electrocorticographic seizure activity and by increases in extracellular glutamate and GABA, as measured by microbore LC in the dialysates. Doses of LY377770, 10-75 mg kg^-1 I.P. (n = 6 at 30 mg kg^-1), or LY382884, 50-150 mg kg^-1 I.P. (n = 6 at 150 mg kg^-1), administered 30 min before pilocarpine perfusion dose-dependently reduced or abolished all the above signs of seizure activity. Similarly, LY377770, 75 mg kg^-1 I.P., dosed immediately after the onset of seizures blocked them within 30 min in all six rats tested. Intrahippocampal perfusion with 75 µM LY377770 before, during and after pilocarpine also prevented the seizure activity (n = 6).

We conclude that the GLUK5 receptor antagonists, LY377770 and LY382884, may have anticonvulsant activity, as indicated by their effect in this model of temporal lobe epilepsy. The precise mode of action will require further elucidation.

Lodge, D. & Bleakman, D. (1998). Neuropharmacology 37, 1187-1204.

Nadler, J.V., Perry, B.W. & Cotman, C.W. (1978). Nature 271, 676-677.

Smolders, I., Khan, G.M., Manil, J., Ebinger, G. & Michotte, Y. (1997). Br. J. Pharmacol. 121, 1171-1179.

Vignes, M., Bleakman, D., Lodge, D. & Collingridge, G.L. (1997). Neuropharmacology 36, 1477-1481.