NMDA receptor activation induces glutamate release through nitric oxide synthesis in guinea pig dentate gyrus.
We tested the hypothesis that the release of glutamate following activation of N-methyl-D-aspartate (NMDA) receptors is mediated by nitric oxide (NO) production, using slices of the guinea pig hippocampus. The NMDA-induced glutamate release from slices of dentate gyrus or CA1, which was both concentration-dependent and Ca(2+)-dependent, was also Mg(2+)-sensitive and abolished by MK-801, a selective non-competitive NMDA receptor antagonist. In dentate gyrus, the NMDA-induced glutamate release was inhibited non-significantly by tetrodotoxin, whereas the NO synthase (NOS) inhibitor NG-nitro-L-arginine (L-NNA) blocked the NMDA-induced release of glutamate in a concentration-dependent manner, but not a high K(+)-evoked release of glutamate. In addition, the L-NNA blockade of NMDA-induced release of glutamate was recovered by pretreatment with L-arginine, the normal substrate for NOS. These results suggest that activation of NMDA receptors in dentate gyrus, as well as subsequent Ca2+ fluxes, is required for the neuronal glutamate release mediated by NO production. On the other hand, the NMDA-evoked glutamate release from CA1 region was tetrodotoxin-sensitive and was not inhibited by L-NNA, thereby suggesting that activation of NMDA receptors in CA1 results in increased glutamate release in an NO-independent manner. Taken together, the NMDA receptor-mediated neuronal release of glutamate from the guinea pig dentate gyrus likely involves the recruitment of NOS activity.
Nei
K
K
Department of Pharmacology, Kobe University School of Medicine, Japan.
Matsuyama
S
S
Shuntoh
H
H
Tanaka
C
C
D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008274:Magnesium / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D013779:Tetrodotoxin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D019335:Nitroarginine; D009569:Nitric Oxide; D018698:Glutamic Acid; D013779:Tetrodotoxin; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; D008274:Magnesium; D002118:Calcium