Tenuifolin attenuates schizophrenia-like be⁃haviors induced by MK-801 via enhancing GABA function in prefrontal cortex

OBJECTIVE Tenuifolin is a natu⁃ral neuroprotective compound isolated from Polygala tenuifolia Willd,which have a long history of being used in mental illness therapy in China.Acute or chronic administration of NMDA recep⁃tor blocker MK-801 is a validated animal model for the positive,negative and cognitive symp⁃toms of schizophrenia.This study aimed to inves⁃tigate the antipsychotic effects and possible mechanism of tenuifolin in MK-801-treated mice.METHODS Sensorimotor gating deficit and hyper⁃locomotion,which implying positive symptoms,were assessed by prepulse inhibition(PPI)test and open field test.Social withdrawal,a main character of negative symptoms,was assessed by social interaction tests.Cognitive deficit was assessed by novel object recognition(NOR)test.The level of glutamate decarboxylase(GAD),GABA and monoamines were detected by West⁃ern blotting or HPLC-ECD.RESULTS Acute administration of MK-801(0.1 mg·kg^(-1),sc)could significantly induce hyperlocomotion and prepulse inhibition(PPI)deficit in mice,which could be reversed by the treatment of tenuifolin(40 and 80 mg·kg^(-1),ig).Moreover,tenuifolin ameliorated social withdrawal and cognitive deficit induced by the chronic administration of MK-801(0.3 mg·kg^(-1) per day,sc,14 d followed by 7 d washout period).In addition,tenuifolin reversed the reduction in GAD and GABA induced by MK-801 and normal⁃ized dopamine,serotonin and norepinephrine in the prefrontal cortex.CONCLUSION These results provided persuasive evidence that tenui⁃folin has multiple antipsychotic-like effects in ani⁃mal model of schizophrenia and its underlying mechanism may be associated with its potential effects on GABA function in the prefrontal cortex.