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 neuronal pathways via release and uptake mechanisms. Stimulation of glutamate receptors induces neuronal nitric oxide (NO) release, which in turn modulates glutamate transmission. In this study, the influence of neuronally derived NO on hippocampal glutamate extracellular concentration was investigated in conditions of intense metabolic activation, i.e., during status epilepticus induced by systemic kainic acid (KA). Glutamate, arginine and citrulline concentrations were measured by microdialysis coupled to HPLC. Experiments were performed in conscious rats implanted with a microdialysis probe within the hippocampal CA3 area. Three groups were used: (1) rats treated with 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 synthase, 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 performed throughout the second hour of status epilepticus. In groups 1 and 3, no significant modifications of extracellular glutamate, arginine and citrulline concentrations were measured. In group 2, the local application of 7-NI in the hippocampus during status epilepticus significantly increased extracellular glutamate and arginine concentrations, whereas citrulline concentration remained constant. The concomitant increases of extracellular glutamate and arginine concentrations under local 7-NI perfusion in seizure conditions, suggest that glutamate and arginine are linked in a common metabolic pathway and/or that glutamate is involved in the cross-talk between glia and neurons. A cerebrovascular effect of 7-NI which triggers glutamate release may also occur.
Alabadí
J A
JA
Laboratoire de Recherches Cérébrovasculaires, CNRS UPR 646, Université Paris VII, France. jose.a.alabadi@uv.es
Thibault
J L
JL
Pinard
E
E
Seylaz
J
J
Lasbennes
F
F
D000818:Animals; D001120:Arginine / Q000032:analysis / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002956:Citrulline / Q000032:analysis / Q000378:metabolism; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000032:analysis / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000503:physiopathology; D007191:Indazoles / Q000494:pharmacology*; D007608:Kainic Acid; D008297:Male; D017551:Microdialysis; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D007191:Indazoles; D002956:Citrulline; D009569:Nitric Oxide; D018698:Glutamic Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D007608:Kainic Acid; C080122:7-nitroindazole