The effects of several metabotropic receptor (mGluR) ligands on baseline hippocampal glutamate and GABA overflow in conscious rats and the modulation of limbic seizure activity by these ligands were investigated. Intrahippocampal mGluR group I agonist perfusion via a microdialysis probe [1 mM (R,S)-3,5-dihydroxyphenylglycine] induced seizures and concomitant augmentations in amino acid dialysate levels. The mGlu 1a receptor antagonist LY367385 (1 mM) decreased baseline glutamate but not GABA concentrations, suggesting that mGlu 1a receptors, which regulate hippocampal glutamate levels, are tonically activated by endogenous glutamate. This decrease in glutamate may contribute to the reported LY367385-mediated anticonvulsant effect. The mGlu 5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (50 mg/kg) also clearly abolished pilocarpine-induced seizures.Agonist-mediated actions at mGlu 2/3 receptors by LY379268 (100 lM, 10 mg/kg intraperitoneally) decreased basal hippocampal GABA but not glutamate levels. This may partly explain the increased excitation following systemic LY379268 administration and the lack of complete anticonvulsant protection within our epilepsy model with the mGlu 2/3 receptor agonist. Group II selective mGluR receptor blockade with LY341495 (1-10 lM) did not alter the rats' behaviour or hippocampal amino acid levels. These data provide a neurochemical basis for the full anticonvulsant effects of mGlu 1a and mGlu 5 antagonists and the partial effects observed with mGlu 2/3 agonists in vivo. Keywords: epilepsy, GABA, glutamate, hippocampus, metabotropic glutamate receptors, microdialysis. Excessive glutamate-mediated processes play a crucial role in seizure generation and maintenance and in excitotoxic epileptic brain damage (Chapman 2000). The actions of most of the existing antiepileptic drugs, however, result in augmentation of GABA-mediated inhibition or in a blockade of voltage-dependent Na + channels. These mechanisms indirectly attenuate excessive glutamate release but also the release of other neuroactive substances. There are only few anticonvulsants known that directly interfere with glutamatergic receptors. Because many intracellular processes are not cell-specific and therefore not easily to target by drugs , the pharmacotherapeutic strategy of choice is still based on intervention with extracellular events. In this study, we present in vivo research data on the modulation of extracellular hippocampal amino acid levels by group I and II metabotropic glutamate receptor (mGluR) ligands, and their concomitant effects on limbic seizures in conscious rats.
Valnoctamide and valpromide (100 mg/kg) proved to be at least as effective as their parent compound sodium valproate (400 mg/kg) against pilocarpine-induced seizures. All three compounds however failed to induce significant initial alterations in extracellular hippocampal GABA release. This questions the enhancement of GABA-mediated inhibition as being one of their mechanisms of action.
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