| Objective Cognitive dysfunction of schizophrenia(SZ)is a difficult clinical treatment.Studies have shown that intranasal administration of oxytocin(OXT)could improve cognitive dysfunction.Disturbance of the OXT-CD38 signaling pathway in the central nervous system may be involved in the pathogenesis of cognitive dysfunction in SZ.In this study,the chronic administration model and developmental model of SZ were established in mice by repeated administration of dizocilpine(MK801)and post weaning social isolation(PWSI),and different doses of OXT were administered intranasally to treat the model mice.Behavioral tests such as social interaction and novel object recognition were used to evaluate the effect of OXT treatment on cognitive function in model mice,and molecular biology techniques such as WB and Elisa were used to detect the expression of OXT-CD38 signaling pathway-related proteins in the hippocampus to explore the possible mechanism of OXT in improving cognitive dysfunction in SZ.Experiment 1Methods 6-week-old C57BL/6J mice were randomly divided into a normal control group(Control group,only given saline)and a model group(only given 0.6 mg/kg MK801),and then the model group was further divided into five groups according to the types of therapeutic drμgs,including no intervention group(MK801-saline group),low-dose OXT administration group(MK801-6 μg/kg OXT group),middle-dose group OXT administration group(MK801-20 μg/kg OXT group),high-dose OXT administration group(MK801-60 μg/kg OXT group)and 0.3 mg/kg risperidone(RIS)administration group(MK801-RIS group).Then,the cognitive function of the mice was evaluated by behavioral tests,and the m RNA and protein expressions of OXT,OXTR and CD38 in the hippocampus of the mice were detected by molecular biology and other techniques(WB,RT-PCR,Elisa).Results(1)Compared with the control group,the social contact index and social exploration ratio of mice in the MK801-saline group were significantly decreased,and the metastasis latency was significantly increased(p<0.05).(2)Compared with the control group,the expressions of OXT m RNA and CD38 protein in the hippocampus of mice in the MK801-saline group were significantly increased(p<0.05).(3)Compared with the MK801-saline group,the social contact index of the MK801-RIS group and the MK801-6 μg/kg OXT group was significantly increased(p<0.05),and the metastasis latency was significantly decreased(p<0.05).Compared with the MK801-saline group,the social exploration ratio of the mice in the MK801-20 μg/kg OXT group and the MK801-60 μg/kg OXT group was significantly increased(p<0.05).(4)Compared with MK801-saline group,the expression of OXT m RNA in hippocampus of mice in MK801-6 μg/kg OXT group,MK801-20 μg/kg OXT group and MK801-60 μg/kg OXT group was significantly decreased(p<0.05).Conclusions(1)Repeated administration of MK801 may induce social and neurocognitive dysfunction in mice,and upregulate the expression of OXT m RNA and CD38 protein in the hippocampus.(2)Three different doses of OXT may alleviate social and neurocognitive dysfunction in MK801-induced SZ model mice to varying degrees,possibly reversing the compensatory up-regulation of OXT-CD38 signaling pathway in the hippocampus of MK801-induced SZ model mice.Experiment 2Methods The 3-week-old C57BL/6J mice were randomly divided into group feeding group(GH-saline group)and PWSI group.The PWSI group was further divided into five groups,including no intervention group(PWSI-saline group),low-dose OXT administration group(PWSI-6 μg/kg OXT group),middle-dose OXT administration group(PWSI-20 μg/kg OXT group),high-dose OXT administration group(PWSI-60 μg/kg OXT group)and 0.3 mg/kg RIS administration group(PWSI-RIS group).Then,the cognitive function of the mice was evaluated by behavior tests,and the m RNA and protein expressions of OXT,OXTR and CD38 in the hippocampus of the mice were detected by molecular biology and other techniques(WB,RT-PCR and Elisa).Results(1)Compared with the GH-saline group,the social exploration ratio and novel object recognition index of the mice in the PWSI-saline group were significantly decreased(p<0.05).(2)Compared with the GH-saline group,the expression of OXTR m RNA in the hippocampus and the concentration of peripheral blood OXT were significantly decreased in the PWSI-saline group(p<0.05).(3)Compared with the PWSI-saline group,the social exploration ratioof the mice in the PWSI-RIS group,PWSI-6 μg/kg OXT group,PWSI-20 μg/kg OXT group and PWSI-60 μg/kg OXT group was significantly increased(p<0.05).Compared with the PWSI-saline group,the novel object recognition index of the PWSI-RIS group and the PWSI-60 μg/kg OXT group was significantly increased(p<0.05).(4)Compared with the PWSI-saline group,the peripheral blood OXT concentration of the mice in the PWSI-20 μg/kg OXT group was significantly increased(p<0.05).Compared with the PWSI-saline group,the expression of OXTR m RNA in the hippocampus of the mice in the PWSI-60 μg/kg OXT group was significantly increased(p<0.01).Conclusions(1)PWSI may induce social and neurocognitive dysfunction in mice,down-regulated the expression level of OXTR m RNA in hippocampus of model mice,and decrease the concentration of OXT polypeptide in peripheral blood.(2)Three different doses of OXT may alleviate neurocognitive and social cognitive dysfunction in PWSI-induced SZ model mice to varying degrees.Moderate and high dose OXT therapy may reverse PWSI-induced down-regulation of hippocampal OXT-CD38 signaling pathway in SZ model mice.18 Figures,7 Tables,127 References... |
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