Regulatory role of nitric oxide over hippocampal 5-HT release in vivo

Previous work has shown that N-methyl-D-aspartate (NMDA) receptor activation decreases 5-hydroxytryptamine (5-HT) release in the hippocampus of freely moving rats. Given the association between NMDA receptor function and nitric oxide (NO) production with the regulation of 5-HT release in other brain regions, we have studied this in rat hippocampus. NMDA (100 microM) decreased hippocampal 5-HT release by approximately 70% and this was reversed by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 10 microM). The NO donor S-nitroso-N-acetylpenicillamine (SNAP) had an inverse concentration-dependent effect on 5-HT release. At 500 microM, SNAP elevated dialysate 5-HT by 55% over basal, while at 5 mM a 70% decrease was seen. The non-selective nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME) at 1 mM increased extracellular 5-HT, although a return to basal levels occurred despite the continued presence of the drug. At 1 mM L-NAME prevented the decrease in 5-HT elicited by NMDA (100 microM) infusion. 7-Nitroindazole (7-NI), a relatively selective neuronal NOS (nNOS) inhibitor, decreased extracellular 5-HT at 100 microM and 1 mM. When 100 microM 7-NI was infused for 60 min prior to NMDA, 5-HT levels were transiently increased above basal before returning to control levels. Following combined application of the two drugs, no decrease in dialysate 5-HT was seen. Our data support a role for NO in modulating both basal and NMDA-evoked changes in 5-HT release in the hippocampus, however, the association appears to be complex. It may be that the recorded changes in 5-HT release are secondary to changes in the release of amino acid transmitters which we have previously found to be dependent on the prevailing extracellular NO concentration.