成瘾物质引起腹侧被盖区多巴胺神经元及其投射脑区伏隔核多巴胺神经递质的实时动力学变化  

Response dynamic of dopamine neurons in ventral tegmental area and dopamine neurotransmitter in nucleus accumbers to addictive drug

作　　者：杨梦蝶 寸兴芳 吴宁 李锦 宋睿 YANG Mengdie;CUN Xingfang;WU Ning;LI Jin;SONG Rui(Nanjing University of Chinese Medicine,Nanjing 210000,China;Beijing Key Laboratory of Neuropsychapharmacology,Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Beijing 100850,China)

机构地区：[1]南京中医药大学,江苏南京210000 [2]军事科学院军事医学研究院毒物药物研究所,神经精神药理学北京市重点实验室,北京100850

出　　处：《中国药理学与毒理学杂志》2023年第11期815-822,共8页Chinese Journal of Pharmacology and Toxicology

基　　金：北京市自然科学基金(7212159)。

摘　　要：目的阐明不同成瘾性物质(甲基苯丙胺、可卡因和吗啡)引起的腹侧被盖区多巴胺神经元及其投射脑区伏隔核内多巴胺递质的实时动力学变化。方法将携带多巴胺神经递质荧光探针和携带酪氨酸羟化酶钙启动子钙指示剂蛋白病毒分别注射在小鼠伏隔核和腹侧被盖区,每个脑区各28只。小鼠分为生理盐水组、甲基苯丙胺(1mg·kg-1,ip)组、可卡因(10mg·kg-1,ip)组和吗啡(10mg·kg-1,sc)组,给药后,立即采用光纤记录系统监测2 h内多巴胺神经递质和多巴胺能神经元的实时动力学变化,包括多巴胺神经递质荧光变化曲线下面积(AUC),曲线极值及达极值的潜伏时间,多巴胺能神经元钙离子信号变化AUC,曲线最高值或最低值及达极值的潜伏时间和作用持续时间。结果ip给予甲基苯丙胺(1 mg·kg-1)和可卡因(10 mg·kg-1)均会引起多巴胺能神经元的Ca2+信号快速而持续地下降,而sc给予吗啡(10 mg·kg-1)引起多巴胺能神经元的Ca2+信号缓慢而持续地上升,甲基苯丙胺给药后的多巴胺能神经元Ca2+信号变化曲线极值和AUC显著低于可卡因(P<0.05);甲基苯丙胺对腹侧被盖区的多巴胺能神经元的持续作用时间显著长于可卡因(P<0.05),而吗啡对腹侧被盖区的多巴胺能神经元持续作用时间显著长于甲基苯丙胺和可卡因(P<0.01,P<0.05)。上述物质引起多巴胺神经递质表现不同,与生理盐水组相比,吗啡、甲基苯丙胺和可卡因均显著诱导小鼠伏隔核内多巴胺显著升高,但也显示了不同的动力学特征:甲基苯丙胺给药后导致的伏隔核脑区多巴胺变化AUC显著高于可卡因和吗啡(P<0.01,P<0.05);甲基苯丙胺和可卡因给药后,多巴胺变化达到极值所需时间显著早于吗啡(P<0.01)。结论不同成瘾性物质对腹侧被盖区多巴胺能神经元的初始作用显著不同,但均可显著升高伏隔核内多巴胺神经递质,并存在动力学变化的显著差异,提示不同种类物�OBJECTIVE To investigate response dynamics of dopamine neurons in the ventral tegmental area(VTA)and dopamine neurotransmitters in the nucleus accumbens(NAc)to methamphetamine,cocaine and morphine.METHODS The dopamine neurotransmitter fluorescent probe was expressed in the NAc of mice(n=28)and the calcium indicator protein carrying the calcium promoter of tyrosine hydroxy-lase was expressed in the VTA of mice(n=28).Then,the mice were equally divided the saline,meth-amphetamine(1 mg·kg-1,ip),cocaine(10 mg·kg-1,ip),and morphine(10 mg·kg-1,sc)into four groups,respectively.Using the fiber-optic recording system,the potency and kinetics of dopamine neurotrans-mitters and dopamine neurons were recorded and analyzed.The paraments included the area under curve(AUC),the peak and the latency time to reach the peak for dopamine neurotransmitter fluores-cent probe in the NAc,besides,the event amplitude and duration were also analyzed for Ca2+signals in the VTA.RESULTS Both injection of methamphetamine andcocaine induced a rapid and sustained decrease of Ca2+signals in dopamine neurons,whereas administration of morphine displayed a slow and sustained increaseof Ca2+signals in dopamine neurons,and the extremes of the change curves in dopaminergic neuronexcitability after methamphetamine administration and the area under the curve were significantly lowerthan those of cocaine(P<0.05);the duration of action of methamphetamine on dopamine neuronsin the VTA was significantly longer than that of cocaine(P<0.05),whereas morphine showed the signifi-cantly longer duration of on dopamine neurons in the VTA compared with both methamphetamine and cocaine(P<0.01,P<0.05).But,all of above drugs significantly increased dopamine neurotransmitters in the NAc compared to saline treatment.However,they still showed different kinetic characteristics.The AUC induced by methamphetamine was significantly higher than cocaine and morphine(P<0.01,P<0.05);moreover,the time to the peak induced by methamphetamine or cocaine was significantly earlier tha

关 键 词：甲基苯丙胺 可卡因 吗啡 多巴胺能神经元 多巴胺递质 

分 类 号：R971[医药卫生—药品]