EXTRACELLULAR CGMP IN THE HIPPOCAMPUS OF FREELY MOVING RATS AS AN INDEX OF NITRIC-OXIDE (NO) SYNTHASE ACTIVITY

The nitric oxide (NO) synthase/cGMP pathway has been studied in vivo i n the adult rat hippocampus by monitoring the levels of extracellular cGMP during microdialysis in conscious unrestrained animals. The basal cGMP efflux was concentration-dependently reduced upon local infusion of the NO synthase inhibitor N-G-nitro-L-arginine (NARG; 10 mu M to 1 mM). The NO donors hydroxylamine and S-nitroso-N- penicillamine, perf used through the dialysis probe at 1 mM, increased by about 200% the e xtracellular levels of cGMP. The glutamate receptor agonist NMDA (125- 500 mu M) produced concentration-dependent cGMP responses that were ab olished by the selective receptor antagonist D-2-amino-5-phosphonovale ric acid or by NARG. Local perfusion of the phosphodiesterase inhibito r 3-isobutyl-1-methylxanthine (IBMX; 1 mM) produced a steady eightfold increase of extracellular cGMP levels. The effect of IBMX was highly sensitive to NARG. The inhibition by NARG of the IBMX-induced cGMP res ponse was reversed when the NO synthase substrate L-arginine was admin istered. It is concluded that cGMP collected during in vivo microdialy sis reflects NO synthase activity in the rat hippocampus. The techniqu e may be utilized to investigate the pathophysiology and the pharmacol ogy of the NO/cGMP pathway in the hippocampus of living animals.