Activation of serotonergic 5-HT1A receptor reduces Ca(2+)- and glutamatergic receptor-evoked arachidonic acid and No/cGMP release in adult hippocampus.
Stimulation of glutamatergic NMDA receptor in adult rat hippocampal synaptoneurosomes induces statistically significant Ca(2+)-dependent liberation of arachidonic acid (AA) and nitric oxide (NO)-activated cGMP synthesis. NMDA acting for 5 min at 100 microM markedly increases, by approx. 25%, Ca(2+)-mediated AA release from phospholipids of hippocampal synaptoneurosomes. Prolonged stimulation of NMDA receptor up to 10 min has smaller stimulatory effect and enhances AA release by about 6%. Moreover, 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 microM). The NMDA-mediated cGMP elevation completely depends on NO action, and is abolished by the specific inhibitor of NO synthase, NG-nitro-L-arginine. Moreover, serotonin at 10 microM in the presence of 10 microM pargyline, potently decreases both Ca(2+)- and NMDA receptor-mediated AA and cGMP release in hippocampal synaptoneurosomes. The agonist of 5-HT1A receptor, buspirone, in a way similar to serotonin itself, counteracts the Ca(2+)- and also NMDA receptor-evoked AA release and cGMP accumulation. An antagonist of 5-HT1A receptor, NAN-190, eliminates the effect of serotonin and buspirone on AA and NO/cGMP liberation. An antagonist 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 system in the hippocampus may play an important role in the modulation of a signal transduction pathway, and by this molecular mechanism serotonin may exert a neuroprotective effect on hippocampal neurons.
Strosznajder
J
J
Laboratory of Cellular Signalling, Polish Academy of Sciences, Warsaw, Poland.
Chalimoniuk
M
M
Samochocki
M
M
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002065:Buspirone / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D019335:Nitroarginine; D016718:Arachidonic Acid; D009569:Nitric Oxide; D012701:Serotonin; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D007650:Ketanserin; D019001:Nitric Oxide Synthase; D011796:Quinacrine; D006152:Cyclic GMP; D002118:Calcium; D002065:Buspirone