• acetylcholine;
  • glutamate;
  • dopamine;
  • kainate;
  • microdialysis;
  • neuroprotection;
  • nitric oxide;
  • NMDA;
  • striatum


The effects of N-methy-d-aspartate (NMDA), kainate, S-α-amino-3-hydroxyd-5-methyl-4-isoxazole propionate (AMPA) and KCI on striatal nitric oxide (NO), acetylcholine (ACh), dopamine (DA), serotonin (5-HT), aspartate (ASP), glutamate (GLU) and γ-aminobutyric acid (GABA) release were measured in anaesthetized rats in vivo by microdialysis and in vitro in organotypic slice cultures. Local NMDA (1–100 μM) infusion by retrodialysis dose-dependently increased levels of classical transmitters, NO2-, NO3-, ctrulline and arginine at similar thresholds (10 γM) Similar patterns of NMDA-evoked (50 μM) release were seen in striatal cultures. NMDA-evoked changes were all calcium-dependent and blocked by NMDA (APV or MK-801) but not AMPN/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 μM but was less potent than NMDA. Kainate also evoked significant Ach1 DA and GLU release dose-dependently starting at 1–10 μM whereas 5-HT, ASP and GABA required 50 or 100 μM 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 μM doses but dose-dependently increased ACh and DA. Similar results were seen with kainate (50 μM) and AMPA (50 μM) in vitro KCI 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 μM) significantly reduced NO2-, NO3- and CIT levels and prevented NMDA, kainate or KCI-evoked increases. It also potentiated ACh, ASP, GLU and GABA release and reduced that of DA in response to 50 μM NMDA whereas treatment with an NO-donor (SNAP; 10 μM) 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 KCI-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. Reduction 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.