NMDA and kainate-evoked release of nitric oxide and classical transmitters in the rat striatum: in vivo evidence that nitric oxide may play a neuroprotective role.
The effects of N-methyl-D-aspartate (NMDA), kainate, S-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and KCl on striatal nitric oxide (NO), acetylcholine (ACh), dopamine (DA), serotonin (5-HT), aspartate (ASP), glutamate (GLU) and gamma-aminobutyric acid (GABA) release were measured in anaesthetized rats in vivo by microdialysis and in vitro in organotypic slice cultures. Local NMDA (1-100 microM) infusion by retrodialysis dose-dependently increased levels of classical transmitters, NO2-, NO3-, citrulline and arginine at similar thresholds (10 microM). Similar patterns of NMDA-evoked (50 microM) release were seen in striatal cultures. NMDA-evoked changes were all calcium-dependent and blocked by NMDA (APV or MK-801) but not AMPA/kainate (DNQX) receptor antagonists, excepting DA which could be prevented by both. In vivo, kainate increased NO2-, NO3-, CIT and ARG levels at 50 and 100 microM but was less potent than NMDA. Kainate also evoked significant ACh, DA and GLU release dose-dependently starting at 1-10 microM whereas 5-HT, ASP and GABA required 50 or 100 microM doses. Kainate effects were inhibited by DNQX, but not by APV, and were calcium-dependent, AMPA failed to alter NO2-, NO3-, CIT or ARG levels at 50 or 100 microM doses but dose-dependently increased ACh and DA. Similar results were seen with kainate (50 microM) and AMPA (50 microM) in vitro. KCl evoked NO2-, NO3-, CIT and ARG release as well as that of the classical transmitters in vivo and in vitro. In vivo administration of the NO synthase inhibitor L-nitroarginine (L-NARG; 100 microM) significantly reduced NO2-, NO3- and CIT levels and prevented NMDA, kainate or KCl-evoked increases. It also potentiated ACh, ASP, GLU and GABA release and reduced that of DA in response to 50 microM NMDA whereas treatment with an NO-donor (SNAP; 10 microM) significantly reduced evoked ACh, ASP and GLU release. The NO synthase inhibitor L-NARG potentiated kainate-evoked ACh release and reduced that of DA, although less potently than NMDA, but it had no effect on KCl-evoked transmitter release. Overall, these results show that both NMDA and kainate increase striatal NO release at similar dose-thresholds as for classical transmitter release suggesting that NO is dynamically released under physiological and not just pathological conditions. Reductions of striatal NO levels also potentiates calcium-dependent transmitter release in response to NMDA and, to a lesser extent, kainate, whereas increasing them reduces it. This is consistent with a role for NO as a neuroprotective agent in this region acting to desensitize NMDA receptors.
Kendrick
K M
KM
Department of Neurobiology, Babraham Institute, Cambridge, UK.
Guevara-Guzman
R
R
de la Riva
C
C
Christensen
J
J
Ostergaard
K
K
Emson
P C
PC
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009569:Nitric Oxide / Q000819:agonists / Q000378:metabolism* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D009569:Nitric Oxide; D016202:N-Methylaspartate; D011189:Potassium Chloride; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D026423:S-Nitroso-N-Acetylpenicillamine; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D007608:Kainic Acid