Serotonin 5HT(1B/1D) receptor agonists abolish NMDA receptor-evoked enhancement of nitric oxide synthase activity and cGMP concentration in brain cortex slices

Our previous studies indicating that the function of excitatory amino acids , NMDA type receptor, is modulated by serotonin focused on the interaction between serotonin 5HT(1B/1D) and glutamate, NMDA receptor in brain cortex. The effect of agonists of 5HT(1B/1D) receptor, sumatriptan, and zolmitripta n on NMDA receptor-evoked activation of nitric oxide (NO) and cGMP synthesi s in adult rat brain cortex slices was investigated. Two kinds of experimen t were carried out using adult rats. In one of them, sumatriptan or zolmitr iptan was administered in vivo subcutaneously (s.c.) in a dose of 0.1 mg pe r kg body weight. Brain slices were then prepared and used in the experimen ts or, in the other exclusively in vitro studies, both agonists at 10 mu M concentration were added directly to the incubation medium containing adult rat brain cortex slices. The data obtained from these studies indicated th at stimulation of NMDA receptor in brain cortex slices leads to a large inc rease in calcium, calmodulin-dependent NO synthase (NOS) activity and to si gnificant enhancement of the cGMP level. This NMDA receptor-dependent NO an d cGMP release was completely blocked by competitive and noncompetitive NMD A receptor antagonists APV (10 mu M) or MK-801 (10 mu M.), respectively. Th e specific inhibitor of Ca2+-dependent isoforms of NOS (N-nitro-1-arginine NNLA and 7-nitroindozole (7-N1)) eliminated the NMDA receptor-mediated enha ncement of NO and cGMP release. Moreover, the serotonin 5HT(1B/1D) receptor agonists sumatriptan and zolmitriptan administrated in vivo (s.c.) or in v itro abolished NMDA receptor-evoked NO signalling in brain cortex. The pote ncy of both agonists investigated directly in vitro was similar to their ef fect after in vivo administration. These results suggest that both serotoni n 5HT(1B/1D) receptor agonists may play an important role in modulating the NO and cGMP-dependent signal transduction pathway in the brain. This effec t of sumatriptan and zolmitriptan on NO signaling in the brain system shoul d be taken into consideration when investigating their mechanism of action in the migraine attack.