NMDA-dependent nitric oxide release in the hippocampus in vivo: interactions with noradrenaline.
Nitric oxide appears to act as a novel intercellular messenger activating soluble guanylyl cyclase to cause an increase in cGMP in target cells. In the nervous system, NMDA receptor activation has often been shown to result in activation of NO synthase, and many of the actions of NMDA are thought to be mediated by NO. We have recently combined intracerebral microdialysis with a sensitive assay for the NO oxidation products nitrite and nitrate, to assess NO release directly in awake, freely-moving animals. In the present study, we have applied this method to the hippocampus, where we have found that local NMDA application increases NO release. This was prevented by prior administration of an NMDA receptor antagonist or a nitric oxide synthase inhibitor. These pretreatments also reduced the basal extracellular nitrite and nitrate levels, suggesting that there may be a tonic glutamate-induced NO production in the hippocampus in awake, freely-moving animals. Previous work on NMDA-induced increases in cGMP suggested a possible role for noradrenaline. We found that pretreatment with the alpha 1A antagonists WB4101 or 5-methyl-urapidil, reduced the basal levels of NO oxidation products, however, NMDA still induced an increase in extracellular NO in the presence of these alpha 1A antagonists. In contrast, prior lesion of the central noradrenergic system with DSP4 prevented the increase in hippocampal NO release seen following local NMDA application. These results indicate that in vivo microdialysis can be used to monitor NO release in the hippocampus in response to NMDA receptor activation.(ABSTRACT TRUNCATED AT 250 WORDS)
Luo
D
D
Kinsmen Laboratory of Neurological Sciences, Department of Psychiatry, University of British Columbia, Vancouver, Canada.
Vincent
S R
SR
D058668:Adrenergic alpha-1 Receptor Antagonists; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D016202:N-Methylaspartate / Q000502:physiology*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D058668:Adrenergic alpha-1 Receptor Antagonists; D001596:Benzylamines; D014179:Neurotransmitter Uptake Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C012102:DSP 4; D009638:Norepinephrine