氟伏沙明在小鼠体内抗抑郁作用的时辰药理学及其机制研究

目的:研究氟伏沙明在小鼠体内抗抑郁作用的时辰药理学及其可能机制。方法:以生理盐水为对照组,考察相邻2天的9:00、13:00、17:00、21:00、1:00、5:00共6个时间点注射氟伏沙明(30mg.kg-1)对小鼠在水中5min内的不动累积时间的影响,和同日内明、暗期(9:00、21:00)注射氟伏沙明对小鼠在暗箱中10min自发性活动(运动距离、运动时间、静止时间)的影响;另外还检测正常小鼠同日内明、暗期(9:00、21:00)脑组织中5羟色胺(5-HT)转运体(SERT)mRNA表达、5-HT再摄取浓度、sigma-1受体的变化。结果:与对照组比较,氟伏沙明能显著缩短小鼠的不动累积时间(P<0.01),其中21:00组不动累积时间最低,但不影响小鼠自发性活动;与明期(9:00)组比较,正常小鼠暗期(21:00)组脑组织中SERTmRNA表达和5-HT再摄取浓度及sigma-1受体的表达均明显升高(P<0.05)。结论:氟伏沙明在小鼠体内的抑郁作用具有昼夜节律性,该作用可能与中脑SERTmRNA的表达、sigma-1受体表达的昼夜节律变化相关。

Study on Chronopharmacology and Its Mechanism of Antidepressant Effect of Fluvoxamine in Mice

OBJECTIVE:To study chronopharmacology and its mechanism of antidepressant effect of fluvoxamine in mice.METHODS:With normal saline as control,the influence of fluvoxamine(30 mg·kg-1) at 9:00,13:00,17:00,21:00,1:00 and 5:00 of consecutive 2 days on the immobility time of mice in water was investigated,and the influence of fluvoxamine at 9:00 and 21:00 on the same day on 10 min spontaneous activity of mice in dark box(movement distance,movement time and rest time) was also studied.Serotonin transporter(SERT) mRNA expression and 5-hydroxytryptamine(5-HT) uptake concentration and sigma-1 receptor in cerebral tissue of normal mice were detected at 9:00 and 21:00 on the same day.RESULTS:Compared with control group,fluvoxamine could shorten the immobility time of mice significantly(P<0.01).The immobility time of mice was the lowest at 21:00,which didn’t influence spontaneous activity of mice.Compared with light phase(9:00) group,SERT mRNA expression,5-HT uptake concentration and sigma-1 receptor expression in cerebral tissue of normal mice increased significantly at dark phase(21:00) group(P<0.05).CONCLUSION:Anti-depressive effect of fluvoxamine exhibits a significant circadian rhythm,the mechanism of which might lie in the time-dependent changes of SERT mRNA expression and sigma receptor expression in the midbrain.