氟西汀不敏感小鼠抑郁行为和脑内白介素-1β表达水平的相关性

Study on correlation between depressive behaviors and brain＇s interleukin-1β level in fluoxetine-insensitive mice

目的 利用对氟西汀不敏感小鼠的抑郁行为模拟难治性抑郁临床表现,并分析其行为和脑内白介素-1β（IL-1β）表达水平之间关系.方法 50只BALB/c小鼠随机分为对照组（Control）,模型组（chronic unpredictable mild stress,CUMS）及模型＋治疗组,分别接受常规饲养9周,CUMS处理9周及CUMS处理8周＋氟西汀处理1周.在第9周结束时,根据氟西汀抗抑郁治疗效果,从模型＋治疗组中筛选出氟西汀疗效不佳小鼠,即治疗抵抗小鼠（antidepressant treatment-resistant mice,ATRM）,以及症状改善小鼠,即一般抑郁小鼠（depression mice,DM）.对Control组、CUMS组、ATRM组以及DM组进行体质量检测、旷场和强迫游泳测试,随后处死动物、提取脑组织进行IL-1β的Elisa检测,比较组间差异.结果 （1）体质量测试：1周盐酸氟西汀抗抑郁治疗未能改善ATRM组小鼠体质量偏低现象.ATRM体质量[（18.56±7.56）g]与CUMS组[（19.03±8.58）g]比较差异无统计学意义,与Control组、DM组小鼠体质量[分别为（24.56±5.45）g,（20.12±9.17）g]比较,差异有统计学意义（P＜0.05）.（2）旷场和强迫游泳实验：旷场实验中,水平运动距离（F=0.355）及进入中心区次数（F=0.327）的组间比较差异无统计学意义;强迫游泳实验中,ATRM游泳不动时间[（241.50±36.55）s]较DM组[（156.00±25.47）s]明显延长（F=13.573,P＜0.05）.（3）脑内IL-1β的Elisa检测结果：ATRM脑内IL-1β水平[（164.90±46.70） pg/mg]显著高于Control组和DM组小鼠[分别为：（72.94±1.44） pg/mg,（93.09±4.65） pg/mg]（P＜0.01）,与CUMS组小鼠相比差异无统计学意义.ATR小鼠的抑郁样行为表现与其脑内IL-1β水平呈正相关（r=0.669,P=0.006）.结论 CUMS可在BALB/c小鼠身上较好地模拟出难治性抑郁针对治疗抵抗的疾病特点,中枢内IL-1β水平的升高可能在难治性抑郁形成中具有重要作用.

Objective To investigate the correlationship between depressed behaviors and interleukin-1β （IL-1β） in brain tissue in mice which are insensitive to fluoxetine,and to mimic the treatment resistant depression （TRD） in clinical condition.Methods 50 BALB/c mice were randomly divided into Control group （Control）,Chronic unpredictable mild stress （CUMS） group and CUMS＋fluoxetine group.Mice in Control group were raised ad libitum for 9 weeks,those in CUMS group received CUMS for 9 weeks and those in CUMS＋fluoxetine group received 8 weeks＇ CUMS followed 1 week＇ s treatment with Fluoxetine（10 mg · kg-1 · d-1）.At the end of the 9th week,mice in（CUMS ＋ treatment）group were selected into antidepressant treatment-resistant mice（ATRM） as no remission and Depression Group （DM） as symptoms improved.Body mass test （BMT）,open field test （OFT） and forces swim test （FST） were completed respectively in these 4 groups at the endpoint of the experiment,and the brain tissue were extracted after the tests for IL-1β Elisa test.Results （1） BMT：there was no effect of weightgain in ATRM after 1 week＇ s therapy with Fluoxetine.There was no difference in body-weight between ATRM （（18.56±7.56） g） and CUMS （（19.03± 8.58） g） mice,while compared with Control （（24.56±5.45） g） and DM mice （（20.12±9.17） g） ATRM and CUMS mile＇s body weight were significantly lower （P＜0.05）.（2）OFT and FST：in OFT,there was no significant difference in of horizontal moving distance（F=0.355） either in the frequencies of entering the central zone （F=0.327） among the 4 groups;in OFT,the immobility time of ATRM （（241.50 ± ± 36.55） s） was significantly longer than that in DM （（156.00± 25.47） s） （F=13.573,P＜0.05）.（3） Elisa test of IL-1β：the brain＇ s IL-1β serum level in ATRM （（164.90±46.70） pg/mg） was higher than those in Control （（69.68±6.56） pg/mg））,and DM （（93.09±4.65） pg/mg） （P＜0.01）,while no difference with that in CUMS mice.Additionally,the depressive behaviors in ATRM showed its positive correlation with the IL-1β level in CNS （r=0.669,P=0.006）.Conclusion CUMS can elicit the refractory depressive symptoms in BALB/c mice to simulate TRD＇ s characteristic,and the elevated level of IL-1 β within brain tissue may play an important role in the development of TRD.