Abstracts

Rationale: During seizures excessive glutamate is released and favors activation of perisynaptic group I metabotropic glutamate receptors (mGluRs). Agonists of these receptors produce seizures and activation of these receptors is implicated in the development of long-lasting changes in excitability that may contribute to epileptogenesis. We evaluated the effects of group I mGluRs antagonists on kindling, a model of epileptogenesis. Methods: Adult male Sprague Dawley Rats (300 gm) were implanted under anesthesia with stimulating electrodes placed in the perforant pathway. Animals were allowed to recover for 2 weeks and then kindled by stimulating at intensities that produced afterdischarges. Animals were treated intraperitoneally 30 minutes before the kindling stimulus was applied with one of the following: the mGluR1 antagonist RS-1-aminoindan-1,5-dicarboxylic acid (AIDA 2 mg/kg), the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP 10 mg/kg), or the combination of the two antagonists. Treatment was only given when the previous stimulation produced an afterdischarge. Control animals received a vehicle injection. The number of stimulations that produced an afterdischarge required to reach stage V kindled seizures were compared. Results: Neither the mGluR1 or mGluR5 antagonist given alone significantly slowed kindling compared to control vehicle treated animals. The combined treatment with both antagonists significantly slowed kindling compared to control animals. Control animals required an average of 11.8 ± 2.1 stimulations with an afterdischarge to reach a class V seizure and 16.7 ± 3.5 stimulations to reach 3 class V seizures. Animals treated with AIDA and MPEP required 20.6 ± 2.8 stimulations to reach the first Class V seizure and 27.7 ± 4.2 stimulations to reach the third class V seizure (p = 0.013). The cumulative duration of afterdischarges was not different between the two groups. Conclusions: The combined antagonism of mGluR1 and 5 receptors retarded kindling while selective antagonists of either receptor alone had no effect. These findings point to a synergistic effect of combined group I mGluR antagonist therapy and implicate a role for both receptors in the development of epilepsy in the kindling model. Supported by VA research.