Serotonin 5HT1B/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 5HT1B/1D and glutamate, NMDA receptor in brain cortex. The effect of agonists of 5HT1B/1D receptor, sumatriptan, and zolmitriptan on NMDA receptor-evoked activation of nitric oxide (NO) and cGMP synthesis in adult rat brain cortex slices was investigated. Two kinds of experiment were carried out using adult rats. In one of them, sumatriptan or zolmitriptan was administered in vivo subcutaneously (s.c.) in a dose of 0.1 mg per kg body weight. Brain slices were then prepared and used in the experiments or, in the other exclusively in vitro studies, both agonists at 10 microM concentration were added directly to the incubation medium containing adult rat brain cortex slices. The data obtained from these studies indicated that stimulation of NMDA receptor in brain cortex slices leads to a large increase in calcium, calmodulin-dependent NO synthase (NOS) activity and to significant enhancement of the cGMP level. This NMDA receptor-dependent NO and cGMP release was completely blocked by competitive and noncompetitive NMDA receptor antagonists APV (10 microM) or MK-801 (10 microM.), respectively. The specific inhibitor of Ca(2+)-dependent isoforms of NOS (N-nitro-1-arginine NNLA and 7-nitroindozole (7-N1)) eliminated the NMDA receptor-mediated enhancement of NO and cGMP release. Moreover, the serotonin 5HT1B/1D receptor agonists sumatriptan and zolmitriptan administrated in vivo (s.c.) or in vitro abolished NMDA receptor-evoked NO signalling in brain cortex. The potency of both agonists investigated directly in vitro was similar to their effect after in vivo administration. These results suggest that both serotonin 5HT1B/1D receptor agonists may play an important role in modulating the NO and cGMP-dependent signal transduction pathway in the brain. This effect of sumatriptan and zolmitriptan on NO signaling in the brain system should be taken into consideration when investigating their mechanism of action in the migraine attack.