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OBJECTIVE To investigate the fast antidepressant effect and the underlying mechanism of it.METHODS C57BL/6 mice were exposed to a 6-week chronic unpredictable mild stress(CUMS)protocol,and treated with YY-23 or a positive drug fluoxetine in the last 3weeks,behavioral assessments proceed every week.NMDA-induced current were recorded by whole-cell patch clamp on dissociated hippocampal CA1 neurons of Sprague-Dawley rats.Phosphorylation of the signaling proteins was evaluated by Western blotting.RESULTS The electrophysiological results showed that YY-23 is a non-competitive NMDA receptor antagonist,neither in′use-dependent′nor′voltage-dependent′way,with no prominent effect on AMPA induced current.This antagonism of YY-23 could be partially prevented by proven blockers MK801 and Mg2+,laterally indicating the nature of NMDA receptor antagonist both pharmacologically and physiologically.Behavioral and Biochemical study showed that YY-23 could act as antidepressant and exerted strong inhibitory effect on GSK3β in PFC of CMS depression mice model.CONCLUSION YY-23 showed promising antidepressant effect with rapid onset,which might be related to NMDA receptor antagonism and GSK3β inhibition.