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

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

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。

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 sig- ma-1 receptor in cerebral tissue of normal mice were detected at 9：00 and 21：00 on the same day. RESULTS： Compared with con- trol 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 ex- pression, 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.