短期氟哌啶醇、利培酮、阿立哌唑作用对小鼠糖脂代谢及行为学影响

Effects of Short-Term Treatment of Haloperidol, Risperidone or Aripiprazole on Gluco-Lipid Metabolism and behaviors in Mice

探究不同抗精神病药物(APDs)短期作用对MK801诱导的精神分裂症模型小鼠体质量、摄食、糖脂代谢以及动物行为学的影响.将60只雄性昆明小鼠随机分成5组,分别给予连续7 d的生理盐水, MK801, MK801加氟哌啶醇(2.0 mg/kg)(HAL), MK801加利培酮(1.0 mg/kg)(RIS), MK801加阿立哌唑(4.0 mg/kg)(ARI)处理.结果显示, MK801诱导的精神分裂症模型组自发活动(旷场实验)较正常组显著增加.模型组小鼠体质量、摄食及糖脂代谢参数均无显著性变化.加入APDs处理后,与模型组比较, 3种药物均能显著降低小鼠的自发活动,该参数与血脂中的甘油三酯(TG)和总胆固醇(TC)的浓度呈显著的负相关;此外, TG浓度还与肝脏组织中重要的转录因子SREBP1c的表达增加呈显著的正相关,与组蛋白受体H1R的表达增加也呈显著的正相关.其中,利培酮表现出较强的引发代谢紊乱的趋势,该药物促进了肝脏组织中SREBP1c和SREBP-2以及H1R的表达显著升高.因此得出,在APDs短期作用下,阿立哌唑无明显糖脂代谢紊乱,具有安全性高、不良反应小的特点.氟哌啶醇的过度镇静效应,可能是这类药物诱发一定程度的代谢性副反应的主要原因;而利培酮作为临床治疗重型精神疾病的一线用药,能较好地发挥疗效,但因其与其他靶点的亲和效应,可能引起更为严重的代谢紊乱副反应,并独立于体质量的增加.

To investigate whether different APDs affect body weight gain, food intake, gluco-lipid metabolism and behaviors after the short-term treatment of haloperidol, risperidone or aripiprazole in a schizophrenic animal model through administration of MK-801, sixty male Kunming mice were randomly divided into 5 groups and treated with vehicle(n=12/group), MK801, MK801 plus haloperidol(2.0 mg/kg), MK801 plus risperidone(1.0 mg/kg) or MK801 plus aripiprazole(4.0 mg/kg) for 7 days. MK801 treatment stimulated hyper-locomotor effects in the open field test. No conspicuous changes in body weight gain, food intake and other gluco-lipid metabolic parameters were observed in the MK801-only treatment group. After APD treatment, a reduction in locomotor behavior was found, which showed a significant negative relationship with plasma triglyceride(TG) and total cholesterol(TC) concentrations. Moreover, a significant positive correlation between plasma TG and hepatic SREBP1c levels as well as Histamine(1) receptor(H1R) levels was observed. Especially, short-term risperidone treatment significantly elevated dyslipidemia, which upregulated the levels of SREBP1c, SREBP-2 and H1R in the liver of mice. In conclusion, aripiprazole has fewer metabolic side effects;haloperidol may cause an over sedation effect, which is probably associated with some metabolic side effects;an increase in hepatic lipogenesis induced by risperidone may be one of the important factors of the metabolic side effects.