ACTIVATION OF SEROTONERGIC 5-HT1A RECEPTOR REDUCES CA2-EVOKED AND GLUTAMATERGIC RECEPTOR-EVOKED ARACHIDONIC-ACID AND NO()CGMP RELEASE IN ADULT HIPPOCAMPUS/

Stimulation of glutamatergic NMDA receptor in adult rat hippocampal sy naptoneurosomes induces statistically significant Ca2+-dependent liber ation of arachidonic acid (AA) and nitric oxide (NO)-activated cGMP sy nthesis. NMDA acting for 5 min at 100 mu M markedly increases, by appr ox. 25%, Ca2+- mediated AA release from phospholipids of hippocampal s ynaptoneurosomes. Prolonged stimulation of NMDA receptor up to 10 min has smaller stimulatory effect and enhances AA release by about 6%. Mo reover, NMDA activates NO-dependent cGMP production by approx. 5 times more than the Ca2+ itself. Release of both these second messengers is completely blocked by the competitive NMDA antagonist, APV (100 mu M) . The NMDA-mediated cGMP elevation completely depends on NO action, an d is abolished by the specific inhibitor of NO synthase, N-G-nitro-L-a rginine. Moreover, serotonin at 10 mu M in the presence of 10 mu M par gyline, potently decreases both Ca2+- and NMDA receptor-mediated AA an d cGMP release in hippocampal synaptoneurosomes. The agonist of 5-HT1A receptor, buspirone, in a way similar to serotonin itself, counteract s the Ca2+- and also NMDA receptor-evoked AA release and cGMP accumula tion. An antagonist of 5-HT1A receptor, NAN-190, eliminates the effect of serotonin and buspirone on AA and NO/cGMP liberation. An antagonis t of serotonergic 5-HT2 receptor, ketanserin, has no effect on the Ca2 + and serotonin action. These results indicate that serotonin, through 5-HT1A receptor, potently antagonizes the action of excitatory amino acid for AA release and NO/cGMP synthesis in the adult rat hippocampus . In conclusion, the interaction of serotonin with the glutamatergic s ystem in the hippocampus may play an important role in the modulation of a signal transduction pathway, and by this molecular mechanism sero tonin may exert a neuroprotective effect on hippocampal neurons. (C) 1 996 Elsevier Science Ltd.