The preferential mGlu2/3 receptor antagonist, LY341495, reduces the frequency of spike-wave discharges in the WAG/Rij rat model of absence epilepsy

Ngomba, R. T. and Biagioni, F. and Casciato, S. and Willems-Van Bree, E. and Battaglia, G. and Bruno, V. and Nicoletti, F. and Van Luijtelaar, E. L. J. M. (2005) The preferential mGlu2/3 receptor antagonist, LY341495, reduces the frequency of spike-wave discharges in the WAG/Rij rat model of absence epilepsy. Neuropharmacology, 49 (SUPPL.). pp. 89-103. ISSN 0028-3908

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Abstract

We examined the expression and function of group-II metabotropic glutamate (mGlu) receptors in an animal model of absence seizures using genetically epileptic WAG/Rij rats, which develop spontaneous non-convulsive seizures after 2–3 months of age. Six-month-old WAG/Rij rats showed an increased expression of mGlu2/3 receptors in the ventrolateral regions of the somatosensory cortex, ventrobasal thalamic nuclei, and hippocampus, but not in the reticular thalamic nucleus and in the corpus striatum, as assessed by immunohistochemistry and Western blotting. In contrast, mGlu2/3 receptor signalling was reduced in slices prepared from the somatosensory cortex of 6-month-old WAG/Rij rats, as assessed by the ability of the agonist, LY379268, to inhibit forskolin-stimulated cAMP formation. None of these changes was found in “pre-symptomatic” 2-month-old WAG/Rij rats. To examine whether pharmacological activation or inhibition of mGlu2/3 receptors affects absence seizures, we recorded spontaneous spike–wave discharges (SWDs) in 6-month-old WAG/Rij rats systemically injected with saline, the mGlu2/3 receptor agonist LY379268 (0.33 or 1 mg/kg, i.p.), or with the preferential mGlu2/3 receptor antagonist, LY341495 (0.33, 1 or 5 mg/kg, i.p.). Injection of 1 mg/kg of LY379268 (1 mg/kg, i.p.) increased the number of SWDs during 3–7 h post-treatment, whereas injection with LY341495 reduced the number of seizures in a dose-dependent manner. It can be concluded that mGlu2/3 receptors are involved in the generation of SWDs and that an upregulation of these receptors in the somatosensory cortex might be involved in the pathogenesis of absence epilepsy.

Keywords:2 amino 2 (2 carboxycyclopropyl) 3 (xanthen 9 yl)propionic acid, 4 amino 2 oxabicyclo3.1.0hexane 4,6 dicarboxylic acid, cyclic AMP, forskolin, metabotropic receptor 2, metabotropic receptor 3, metabotropic receptor agonist, metabotropic receptor antagonist, sodium chloride, absence, animal cell, animal experiment, animal model, animal tissue, article, brain region, brain slice, corpus striatum, disease model, dose response, hippocampus, immunohistochemistry, inhibition kinetics, injection, male, nonhuman, priority journal, protein expression, protein function, rat, rat strain, receptor upregulation, recording, seizure, signal transduction, somatosensory cortex, spike wave, stimulation, thalamus nucleus, tissue preparation, Western blotting, Age Factors, Amino Acids, Analysis of Variance, Animals, Baclofen, Behavior, Animal, Blotting, Western, Brain, Brain Mapping, Circadian Rhythm, Disease Models, Animal, Electroencephalography, Epilepsy, Absence, Excitatory Amino Acid Antagonists, GABA Agonists, Glial Fibrillary Acidic Protein, Indoles, Microdialysis, Motor Activity, Rats, Rats, Inbred Strains, Receptors, Metabotropic Glutamate, Xanthenes
Subjects:B Subjects allied to Medicine > B210 Pharmacology
B Subjects allied to Medicine > B140 Neuroscience
Divisions:College of Science > School of Pharmacy
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ID Code:22162
Deposited On:18 Feb 2016 15:32

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