NMDA RECEPTOR ACTIVATION IN RAT HIPPOCAMPUS INDUCES CYCLIC-GMP FORMATION THROUGH THE L-ARGININE NITRIC-OXIDE PATHWAY

When slices of young rat hippocampus were exposed briefly (2 min) to N-methyl-D-aspartate (NMDA), a rise in the levels of cyclic GMP took place. This response was dependent on NMDA concentration (IC50 almost-equal-to 30-mu-M) and the maximal elevations exceeded the unstimulated levels by 25-fold. The response to 100-mu-M NMDA was inhibited by two competitive antagonists of the conversion of arginine to nitric oxide, L-N(G)-methylarginine and L-N(G)-nitroarginine (IC50 approximately 6-mu-M and 100 nM respectively). The inhibitions produced by both antagonists were reduced or abolished when the incubation medium was supplemented with L-arginine (100-300-mu-M). Slices of adult hippocampus produced smaller increases (5-fold) in cyclic GMP levels in response to 100-mu-M NMDA than those found in the immature tissue, but the response could similarly be inhibited by N(G)-methylarginine. The results indicate that NMDA receptor activation in the hippocampus induces the generation of nitric oxide from arginine and that this novel intercellular messenger mediates the increases in cyclic GMP levels.