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

Previous work has shown that N-methyl-D-aspartate (NMDA) receptor activatio n decreases 5-hydroxytryptamine (5-HT) release in the hippocampus of freely moving rats. Given the association between NMDA receptor function and nitr ic oxide (NO) production with the regulation of 5-HT release in other brain regions, we have studied this in rat hippocampus. NMDA (100 muM) decreased hippocampal 5-HT release by approximately 70% and this was reversed by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 10 muM). The NO donor S-nitroso-N-acetylpenicillamine (SNAP) had an inverse concentr ation-dependent effect on 5-HT release. At 500 muM, SNAP elevated dialysate 5-HT by 55% over basal, while at 5 mM a 70% decrease was seen. The non-sel ective nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl este r (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 muM) infusion. 7-Nitr oindazole (7-NI), a relatively selective neuronal NOS (nNOS) inhibitor, dec reased extracellular 5-HT at 100 CIM and 1 mM. When 100 CIM 7-NI was infuse d for 60 min prior to NMDA, 5-HT levels were transiently increased above ba sal before returning to control levels. Following combined application of t he two drugs, no decrease in dialysate 5-HT was seen. Our data support a ro le 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 th e release of amino acid transmitters which we have previously found to be d ependent on the prevailing extracellular NO concentration.