抗精神病药干预早期社会隔离小鼠精神分裂样表型的机制研究

The mechanism of antipsychotics interfering with schizophrenic-like phenotype in early social isolation mice

目的探讨并比较利培酮和氟哌啶醇对早期社会隔离小鼠的作用及机制。方法C57BL/6小鼠,实验组小鼠3周离乳后单笼单养进行社会隔离(SI),对照(GH)组正常饲养。8周成年后,分别腹腔注射等体积的生理盐水(NS)、利培酮(RIS)和氟哌啶醇(HA)。小鼠分为4组:GH+NS、SI+NS、SI+RIS、SI+HA。利培酮和氟哌啶醇的剂量分别为0.1、0.2 mg/kg。给药14 d后,通过旷场实验、高架十字迷宫实验、强迫游泳实验、筑巢实验、社会交往实验、新异物体辨别实验、前脉冲抑制实验,从自主活动、情绪、认知、社会行为等方面评估小鼠的精神分裂样行为,并检测前额叶皮质(PFC)和伏隔核(NAc)中多巴胺2型受体(D2R)、1-亚基N-甲基-D-天冬氨酸受体(NR1)。结果与GH组相比,SI组小鼠焦虑、抑郁样行为明显增加(P<0.05),筑巢能力明显下降(P<0.05),社会交往及躲避行为明显减少(P<0.05),PPI认知功能受损(P<0.05);与氟哌啶醇相比,利培酮不仅对抑郁样行为和PPI受损有改善,也对焦虑样行为、筑巢能力、社会互动及逃避行为有所改善;SI+RIS和SI+HA组小鼠的NAc中D2R含量明显下降,PFC中NR1的含量相较于GH组的统计学差异消失。结论早期SI是较好的模拟精神分裂的模型;相比氟哌啶醇,利培酮具有更好的干预效果;利培酮和氟哌啶醇可能是通过D2R、NR1发挥作用的。

Objective To investigate and compare the effects and mechanisms of risperidone and haloperidol on early socially isolated mice.Methods C57BL/6 mice aged 3 weeks were raised in single cages after weaning for social isolation(SI),and the control(GH)group was raised normally.Eight weeks later(mouse adult),the mice received intraperitoneal injection of equal volumes of normal saline(NS),risperidone(RIS)and haloperidol(HA).Then they were divided into four groups:GH+NS,SI+NS,SI+RIS,and SI+HA.The dose of risperidone and haloperidol was 0.1 mg/kg and 0.2 mg/kg,respectively.After administration for 14 days,through the open field experiment,elevated plus maze experiment,forced swimming experiment,nesting experiment,social interaction experiment,novel object discrimination experiment,and prepulse suppression experiment,the mice’s schizophrenia-like behavior was evaluated in terms of autonomous activities,emotions,cognition,and social behavior.We also detected dopamine type 2 receptor(D2R)and the N-methyl-D-aspartate receptor subunit NR1 in the prefrontal cortex(PFC)and nucleus accumbens(NAc).Results Compared with those in GH group,the anxiety-like behavior and depression-like behavior of SI mice were significantly increased(P<0.05),while the nesting ability was significantly decreased(P<0.05)and social interaction and avoidance behavior were significantly reduced(P<0.05);the cognitive function of PPI was impaired(P<0.05).Compared with haloperidol,risperidone improved not only depression-like behavior and PPI impairment,but also anxiety-like behavior,nesting ability,social interaction,and avoidance behavior.In SI+RIS and SI+HAL groups,the content of D2R in NAC decreased significantly,and the difference of NR1 in PFC disappeared compared with the control group.Conclusion Early SI is a good model for simulating schizophrenia.Risperidone has a better intervention effect than haloperidol;risperidone and haloperidol may exert their effects through D2R and NR1.