甲基苯丙胺的神经毒性及5-羟色胺转运体信使RNA的表达

Neurotoxicity of methamphetamine and the expression of serotonin transporter mRNA

目的:观察甲基苯丙胺诱导实验大鼠的神经毒性及大鼠各脑区5-羟色胺转运体信使RNA的表达,寻找有效的神经保护性药物。方法:实验于2002-08/12在四川大学实验动物中心、四川大学华西医院分子病理实验室(四川省重点实验室)完成。选择Wistar雄性大鼠20只,随机分为对照组和实验组,每组10只。实验组给予甲基苯丙胺[20mg/kg,腹腔注射,每天两次(8:00,20:00),连续4d],对照组给予等体积生理盐水。采用高效液相色谱法测定各组大鼠不同脑区的多巴胺、5-羟色胺含量的改变,原位杂交方法检测5-羟色胺转运体信使RNA的表达。结果:20只大鼠均进入结果分析。①末次给药后第7天,实验组大鼠额叶皮质、海马和纹状体的5-羟色胺均有下降(P<0.05),在3个脑区的下降率分别为58.09%,56.76%和25.51%;额叶皮质和纹状体的多巴胺含量有一定降低(P<0.05),下降率分别为16.58%和22.28%,,而海马的多巴胺含量无明显变化(P>0.05)。②末次给药后第7天,实验组大鼠额叶皮质、海马和纹状体的5-羟色胺转运体信使RNA的表达均有一定程度的降低(P<0.05),分别下降60.87%,72.59%和36.50%。结论:甲基苯丙胺对实验大鼠的中枢5-羟色胺、多巴胺系统具有明显的神经毒性,并导致5-羟色胺转运体信使RNA表达的下调。

AIM： To observe the neurotoxicity of experimental rats induced by metbamphetamine and the expression of serotonin transporter mRNA of rats brain, so as to find out effective neuroproteetive drugs. METHODS： The experiment was carried out in the center of experimental animals in Sichuan University, and the molecular pathology laboratory of West China Hospital of Sichuan University （Sichuan provincial key laboratory） from August to December 2002. Twenty male Wistar rats were randomly divided into control group （n =10） and experimental group （n=10）. Rats in the experimental group were injected with methamphetamine intraperitoneally （20 mg/kg, twice a day at 8：00 and 20：00 respectively for 4 continuous days）, and those in the control group were administered with saline of the same volume. The changes of the contents of dopamine and serotonin in the rats＇ brain in each group were measured by high performance liquid chromatography （HPLC）, and the expression of serotonin transporter mRNA was detected by in situ hybridization. RESULTS： All the 20 rats were involved in the analysis of results. （1） On the 7^th day after the last administration, the serotonins in rats＇ frontal cortex, hippocampus and striatum in the experimental group were all decreased as compared with those in the control group （P 〈 0.05）, and the rate of decrease in the three brain regions was 58.09%, 56.76% and 25.51% respectively; the contents of dopamine in rats＇ frontal cortex and striatum were all decreased as compared with those in the contral group （P 〈 0.05）, and the rate of decrease in the two brain regions was 16.58% and 22,28% respectively, but the content dopamine in hippocampus had no obvious change （P 〉 0.05）. （2） On the 7^th day alter the last administration, the expressions of scrotonin transporter mRNA in rats＇ frontal cortex, hippocampus and striatum were all down-regulated significantly in the experimental group as compared with those in the control group （P 〈 0.05）, and the rate of decrease in the three brain regions was 60.87%, 72.59% and 36.50% respectively. CONCLUSION： Methamphetamine can cause neurotoxicity to serotonin and dopamine systems in the central nervous system of experimental rats, and down-regulates the expression of serotonin transporter mRNA.