2 PATHWAYS OF NITRIC-OXIDE PRODUCTION THROUGH GLUTAMATE RECEPTORS IN THE RAT CEREBELLUM IN-VIVO

The effects of N-methyl-D-aspartate (NMDA), lpha-amino-3-hydroxy-5-met hylisoxazole-4-propionic acid (AMPA), and trans-(+/-)-1-amino-(1S,3R)- cyclopentanedicarboxyl acid (ACPD) on nitric oxide (NO) production in the cerebellum of conscious rats were investigated by measuring the le vels of total NO metabolites (nitrite plus nitrate, NOx-) in dialysate s obtained by in vivo microdialysis. All glutamate receptor agonists d ose-dependently increased NOx- levels. Pharmacological characterizatio n with various glutamate receptor antagonists indicated that the effec ts of NMDA, AMPA and ACPD are mediated by NMDA, non-NMDA, and L(+)-2-a mino-3-phosphonopropionic acid (L(+)-AP-3)-sensitive metabotropic glut amate receptors, respectively. The NO synthase (NOS) inhibitors, inclu ding N-G-nitro-L-arginine methyl ester (L-NAME), N-G-nitro-L-arginine (L-NA), 7-nitroindazole (7-NI), and N-G-monomethyl-L-arginine, inhibit ed NMDA-induced, but not AMPA- or ACPD-induced, increase in NOx- level s. L-Arginine enhanced NMDA-induced, but not AMPA- or ACPD-induced, in crease in NOx- levels. Cytochrome P-450 inhibitors, SKF525A and erythr omycin, inhibited the effect of NMDA, but not AMPA or ACPD. These resu lts suggest that AMPA and ACPD may induce NO production through a NOS- independent pathway although NMDA receptor-mediated NO production is d ependent on NOS activity in the rat cerebellum in vivo. (C) 1997 Elsev ier Science Ireland Ltd.