title: Phenotypic differences between fast and slow methionine sulfoximine-inbred mice: seizures, anxiety, and glutamine synthetase.
abstract: Seizures induced by the convulsant methionine sulfoximine (MSO) resemble human "grand mal" epilepsy, and brain glutamine synthetase is inhibited. We recently selected two inbred lines of mice: sensitive to MSO (MSO-Fast) and resistant (MSO-Slow). In the present study, the selection pressure was increased and consanguinity established. To gain insight into the mechanisms of epileptogenesis, we studied the behaviour of MSO-Fast and MSO-Slow mice based on their responses to various convulsants and anticonvulsants, and also the kinetics of glutamine synthetase. The results show that increasing the number of generations of sib-crossings resulted in an increase in the differences between MSO-Fast and MSO-Slow mice. The dose-response curve of MSO-dependent seizures demonstrated that the MSO-Slow mice were highly insensitive to MSO-dependent seizures compared with MSO-Fast inbred mice that were highly sensitivity. The MSO-Slow were resistant to convulsions induced by various convulsants having different mechanisms of action, whereas those in the MSO-Fast line were more sensitive to kainic acid-induced seizures. These data, in addition to the effects of anticonvulsant, strongly suggest that glutamatergic pathways are most likely involved in MSO-dependent seizures, rather than GABAergic ones. This hypothesis is corroborated by the glutamine synthetase activity, which is more elevated in the MSO-Slow line. Behaviour tests showed that MSO-Slow were less anxious than MSO-Fast. Collectively, these results showed that glutamatergic pathways could be involved in the epileptogenic action of MSO, which may be related to the glutamate/glutamine cycle in the brain.
authors: Laboratoire de Neurobiologie, Rue de Chartres, Université d'Orléans, 45067 Orléans CEDEX 2, France.
authors: Arnaud
authors: A
authors: Boissonnet
authors: Tobias
authors: T
authors: Hévor
authors: Jean-François
authors: JF
authors: Cloix
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D008297:Male; D008717:Methionine Sulfoximine / Q000008:administration & dosage*; D051379:Mice; D008815:Mice, Inbred Strains; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism
chemical_list: D008717:Methionine Sulfoximine; D005974:Glutamate-Ammonia Ligase