7-nitroindazole, a selective inhibitor of nNOS, increases hippocampal extracellular glutamate concentration in status epilepticus induced by kainic acid in rats

The glutamate extracellular concentration is controlled by metabolic and ne uronal pathways via release and uptake mechanisms. Stimulation of glutamate receptors induces neuronal nitric oxide (NO) release, which in turn modula tes glutamate transmission. In this study, the influence of neuronally deri ved NO on hippocampal glutamate extracellular concentration was investigate d in conditions of intense metabolic activation, i.e., during status epilep ticus induced by systemic kainic acid (KA). Glutamate, arginine and citrull ine concentrations were measured by microdialysis coupled to HPLC. Experime nts were performed in conscious rats implanted with a microdialysis probe w ithin the hippocampal CA3 area. Three groups were used: (I) rats treated wi th KA i.p. (12 mg/kg) and vehicle locally, via the microdialysis probe (n = 9); (2) rats given KA i.p. and a selective inhibitor of neuronal NO syntha se, 7-nitroindazole (7-NI, 1.25 mM) locally (n = 13); (3) rats treated with saline i.p. and 7-NI locally (n = 7). Infusion of 7-NI or vehicle was perf ormed throughout the second hour of status epilepticus. In groups 1 and 3, no significant modifications of extracellular glutamate, arginine and citru lline concentrations were measured. In group 2, the local application of 7- NI in the hippocampus during status epilepticus significantly increased ext racellular glutamate and arginine concentrations, whereas citrulline concen tration remained constant. The concomitant increases of extracellular gluta mate and arginine concentrations under local 7-NI perfusion in seizure cond itions, suggest that glutamate and arginine are linked in a common metaboli c pathway and/or that glutamate is involved in the cross-talk between glia and neurons. A cerebrovascular effect of 7-NI which triggers glutamate rele ase may also occur. (C) 1999 Elsevier Science B.V. All rights reserved.