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-h ydroxy-5-methyl-4-isoxazole propionate (AMPA) and KCl on striatal nitr ic oxide (NO), acetylcholine (ACh), dopamine (DA), serotonin (5-HT), a spartate (ASP), glutamate (GLU) and gamma-aminobutyric acid (GABA) rel ease were measured in anaesthetized rats in vivo by microdialysis and in vitro in organotypic slice cultures. Local NMDA (1-100 mu M) infusi on by retrodialysis dose-dependently increased levels of classical tra nsmitters, NO2-, NO3-, citrulline and arginine at similar thresholds ( 10 mu M) Similar patterns of NMDA-evoked (50 mu M) release were seen i n striatal cultures. NMDA-evoked changes were all calcium-dependent an d 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 mu M bu t was less potent than NMDA. Kainate also evoked significant ACh, DA a nd GLU release dose-dependently starting at 1-10 mu M whereas 5-HT, AS P and GABA required 50 or 100 mu M doses. Kainate effects were inhibit ed by DNQX, but not by APV, and were calcium-dependent. AMPA failed to alter NO2-, NO3-, CIT or ARG levels at 50 or 100 mu M doses but dose- dependently increased ACh and DA. Similar results were seen with kaina te (50 mu M) and AMPA (50 mu M) in vitro. KCI evoked NO2-, NO3-, CIT a nd ARG release as well as that of the classical transmitters in vivo a nd in vitro. In vivo administration of the NO synthase inhibitor L-nit roarginine (L-NARG; 100 mu M) significantly reduced NO2-, NO3- and CIT levels and prevented NMDA, kainate or KCI-evoked increases. It also p otentiated ACh, ASP, GLU and GABA release and reduced that of DA in re sponse to 50 mu M NMDA whereas treatment with an NO-donor (SNAP; 10 mu M) significantly reduced evoked ACh, ASP and GLU release. The NO synt hase inhibitor L-NARG potentiated kainate-evoked ACh release and reduc ed that of DA, although less potently than NMDA, but it had no effect on KCI-evoked transmitter release. Overall, these results show that bo th NMDA and kainate increase striatal NO release at similar dose-thres holds as for classical transmitter release suggesting that NO is dynam ically released under physiological and not just pathological conditio ns. Reduction of striatal NO levels also potentiates calcium-dependent transmitter release in response to NMDA and, to a lesser extent, kain ate, whereas increasing them reduces it. This is consistent with a rol e for NO as a neuroprotective agent in this region acting to desensiti ze NMDA receptors.