Differential effects of NMDA and AMPA/kainate receptor antagonists on nitric oxide production in rat brain following intrahippocampal injection

Stimulation of glutamate receptors induces neuronal nitric oxide (NO) release, which in turn modulates glutamate transmission. The involvement of ionotropic glutamate NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainite (KA) receptors in the induction of NO production in the rat brain was examined after injection of kainate, non-NMDA receptor agonist, KA + 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), selective AMPA/KA receptor antagonist, or KA + 2-amino-5-phosphonopentanoic acid (APV), selective NMDA receptor antagonist. Competitive glutamate receptor antagonists were injected with KA unilaterally into the CA3 region of the rat hippocampus. The accumulation of nitrite, the stable metabolite of NO, was measured by the Griess reaction at different times (5 min, 15 min, 2 h, 48 h and 7 days) in the ipsi- and contralateral hippocampus, forebrain cortex, striatum and cerebellum homogenates. The detected increase of NO production in distinct brain regions, which are functionally connected via afferents and efferents, suggests that these regions are affected by the injury. The effect of KA on nitrite production was blocked by the glutamate antagonists. Intrahippocampal KA + CNQX injection resulted in decrease of nitrite production, around control levels, in all tested brain structures. Significant decrease in nitrite levels was found only in comparison to KA-treated animals, i.e. the overall effect of selective AMPA/KA receptor antagonist was a decrease of KA-induced excitotoxicity. The accent effect of intrahippocampal KA + APV injection resulted, also, in decrease of nitrite production. However, this effect was detected after 5 min from the injection indicating the existence of an NMDA receptor-mediated component of basal nitrite production in physiological conditions and difference in mechanisms and time dynamics between CNQX and APV. The used antagonists showed same pattern in all tested brain structures. APV and CNQX both expressed sufficient neuroprotection in sense of reducing nitrite concentrations, but with differential effect in mechanisms and time dynamics. Our findings suggest that NMDA and AMPA/KA receptors are differentially involved in NO production.