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Aim: To examine whether (-)-stepholidine (SPD) has a direct effect on the N-methyl-D-aspartic acid receptors (NMDAR) containing the NMDA receptor sub-units NR2A or NR2B and to compare its effect with those of haloperidol (Hal) andclozapine (Cloz). Methods: NMDAR was transiently expressed in human embry-onic kidney 293 (HEK293) cells. Changes in intracellular calcium concentration([Ca2+]I) induced by NMDAR activation were monitored with Fura-2 ratio imagingtechniques. Results: SPD had no significant effects on either subunit of NMDARat a concentration of less than 100 μmol/L. Hal selectively inhibited NMDARcontaining the NR2B subunit, whereas Cloz inhibited both subunits of NMDAR.Although both Hal and Cloz inhibited NR1a/NR2B receptor-mediated Ca2+ influx,their effects were different. Hal was more potent and had a faster peak effect thanCloz. Conclusion: Both Hal and Cloz inhibit NMDAR-mediated function, whereasSPD produced only a little inhibition at a high concentration. Based on our otherstudies, the modulation of SPD on NMDAR function may be via D1 receptoraction underlying an indirect mechanism.