The effects of N-methyl-D-aspartate (NMDA), (+)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and trans-(±)-1-amino-(1S,3R)-cyclopentanedicarboxylic acid (ACPD) on nitric oxide (NO) production in the cerebellum of conscious rats were investigated by measuring the levels of total NO metabolites (nitrite plus nitrate, NO(x)-) in dialysates obtained by in vivo microdialysis. All glutamate receptor agonists dose-dependently increased NO(x)- levels. Pharmacological characterization with various glutamate receptor antagonists indicated that the effects of NMDA, AMPA and ACPD are mediated by NMDA, non-NMDA, and L(+)-2-amino-3-phosphonopropionic acid (L(+)-AP-3)-sensitive metabotropic glutamate receptors, respectively. The NO synthase (NOS) inhibitors, including N(G)-nitro-L-arginine methyl ester (L-NAME), N(G)-nitro-L-arginine (L-NA), 7-nitroindazole (7-NI), and NO-monomethyl-L-arginine, inhibited NMDA-induced, but not AMPA- or ACPD-induced, increase in NO(x)- levels. L-Arginine enhanced NMDA-induced, but not AMPA- or ACPD-induced, increase in NO(x)- levels. Cytochrome P-450 inhibitors, SKF525A and erythromycin, inhibited the effect of NMDA, but not AMPA or ACPD. These results suggest that AMPA and ACPD may induce NO production through a NOS-independent pathway although NMDA receptor-mediated NO production is dependent on NOS activity in the rat cerebellum in vivo.
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