甲基苯丙胺依赖鼠相关脑区多巴胺转运体、D1和D2受体、五羟色胺转运体表达及依赖机制研究
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摘要
目的:建立甲基苯丙胺依赖大鼠模型,对甲基苯丙胺依赖大鼠额叶皮质、伏隔核、纹状体、海马、黑质、中脑腹侧被盖六个相关脑区多巴胺转运体(DAT)、多巴胺受体D1(DRDl)、多巴胺受体D2(DRD2)、五羟色胺转运体(SERT)表达的变化进行研究,探讨六个脑区上述指标的变化与甲基苯丙胺依赖机制的关系。方法:SD大鼠160只,随机分为对照组、依赖一周、两周、四周及八周组,实验组经腹腔注射甲基苯丙胺10天后,进行刻板行为和条件性位置偏爱实验观察,确认甲基苯丙胺依赖后,分别再注射一周、两周、四周和八周,建立不同依赖时间段的依赖大鼠模型。脑区取材后,应用免疫组化技术、原位杂交技术、蛋白质免疫印迹技术和逆转录PCR技术检测六个脑区DAT、DRD1、DRD2、SERT蛋白质及其mRNA的变化,对上述指标的变化进行定位、定量研究,采用方差分析统计实验结果。结果:与对照组比较,四个实验组的条件性位置偏爱实验均有显著性差异(P＜0.05)。在不同实验组相同脑区,DAT、DRD1、DRD2、SERT表达均有变化。在额叶皮质,DAT依赖一周组明显下降,到两周时有轻度回升并持续到四周,八周时又下降,对照组和一周组、两周组、八周组比较,四周组和八周组比较有统计学意义(P＜0.05)。DRD1依赖一周组明显下降,两周时明显回升并持续到四周,八周时又明显下降。对照组、一周组和四周组比较有统计学意义(P＜0.05)。DRD2依赖一周组明显升高,两周时轻度下降并持续到四周,八周时又明显升高。对照组和一周组、两周组、八周组比较、一周组和四周组比较、四周组和八周组比较有统计学意义(P＜0.05)。SERT依赖一周组明显下降并持续至两周,四周时升高,八周时又稍下降。对照组和一周组、两周组比较有统计学意义(P＜0.05)。
在伏隔核,DAT依赖一周组明显下降并持续到两周,四周时又明显回升,到八周时又出现轻度下降。对照组和一周组、两周组、八周组比较、一周组和四周组比较、两周组和四周组、八周组比较有统计学意义(P＜0.05)。DRD1依赖一周组至八周均表现为升高,但组间两两比较均无统计学差异。DRD2依赖一周组明显升高并持续到两周,四周时开始下降,八周时又明显升高。对照组和一周组、两周组、八周组比较、四周组和八周组比较有统计学意义(P＜0.05)。SERT依赖一周组明显下降,持续至两周,四周时明显升高,八周时又稍下降。对照组和一周组、两周组比较、一周组和四周组、八周组比较、两周组和四周组、八周组比较有统计学意义(P＜0.05)。在纹状体,DAT依赖一周组明显下降,两周组轻度回升并持续到四周,八周组出现轻度下降。对照组和一周组、两周组、八周组比较有统计学意义(P＜0.05)。DRD1依赖一周至八周,均呈下降趋势,但组间两两比较均无统计学差异。DRD2依赖一周组明显升高并持续到两周,四周组下降并持续到八周。对照组、一周组和两周组比较有统计学意义(P＜0.05)。SERT依赖一周后下降并持续至两周,四周时则开始升高,到八周时又再次下降。对照组和两周组、四周组、八周组比较、一周组和两周组比较有统计学意义(P＜0.05)。在海马,DAT依赖一周组升高,到两周时下降并持续到四周,八周时又轻度升高。但组间两两比较均无统计学差异。DRD1依赖一周组升高,两周时下降并持续到四周,到八周时又回升,但组间两两比较均无统计学差异。DRD2依赖一周组明显下降,两周时逐渐回升并持续至八周,对照组和一周组、两周组、四周组、八周组比较均有统计学意义(P＜0.05)。SERT依赖一周组下降并持续至两周,四周时开始升高,到八周时又再次下降。对照组、一周组和两周组比较、两周组和一周组、四周组比较有统计学意义(P＜0.05)。在中脑腹侧被盖,DAT依赖一周到八周均升高,对照组与四周组、八周组有统计学差异(P＜0.05)。DRD1依赖一周组升高并持续到两周、四周,到八周时稍下降,组间两两比较均无统计学差异。DRD2依赖一周组明显升高并持续到两周,四周时开始下降并持续到八周。对照组和两周组比较有统计学意义(P＜0.05)。SERT依赖一周组下降,至两周时明显回升,四周时又明显下降并持续至八周。对照组和一周组、四周组、八周组比较、两周组和四周组、八周组比较有统计学意义(P＜0.05)。在黑质,DAT依赖一周组下降,两周组明显升高,四周时明显下降并持续至八周,两周组与四周组、八周组比较有统计学意义(P＜0.05)。DRD1依赖一周组升高,两周时稍下降,从四周开始回升并持续至八周,但组间两两比较均无统计学差异。DRD2依赖一周组升高,两周时开始下降并持续至四周,八周时又逐渐回升,但组间两两比较均无统计学差异。SERT依赖一周组下降并持续至两周,四周时明显回升,八周时又稍下降。对照组和一周组、两周组、四周组、八周组比较有统计学意义(P＜0.05)。在同一实验组的不同脑区,DAT、DRD1、DRD2、SERT表达呈现不同的变化趋势,部分脑区之间表达具有统计学差异(P＜0.05)。结论:1.采用多次腹腔注射甲基苯丙胺,结合条件性位置偏爱实验的方法成功建立甲基苯丙胺依赖大鼠模型;2.在额叶皮质、伏隔核、纹状体、海马、中脑腹侧被盖、黑质六个脑区多巴胺转运体、多巴胺受体D1、多巴胺受体D2、五羟色胺转运体的表达存在明显变化,并且不同脑区之间和不同依赖时间段之间的表达存在一定差异,多巴胺转运体、多巴胺受体D1、多巴胺受体D2、五羟色胺转运体的表达变化与甲基苯丙胺依赖机制有密切关系。
Objective:To establish a rat model of methamphetamine(MA)dependence,then detect the expression of dopamine transporter(DAT),dopamine receptor D 1(DRD1), dopamine receptor D2(DRD2),and serotonin transporter(SERT)in six cerebral regions which related to MA dependence.Then investigate the correlation between the expression of DAT,DRD1,DRD2 and SEPT with the mechanism of MA dependence.Methods:The rats were devided into five groups which were control group,1 week group,2 weeks group,4 weeks group,and 8 weeks group of MA dependence.The models of diffenrent periods of administered MA(ip,10mg.kg-1 per day)were established.Then observe the stereotyped behavior and do experiment of conditioned position preference(CPP)to confirm the models were successfully esablished.The animals were sacrificed,the brain tissues of the prefrontal cortex, nucleus accumbens septum,striatum,hippocampus,ventral tegmental area,and substantia nigra were collected to detect the expression of DAT,DRD1,DRD1,SERT with the methods of immunohistochemistry,in situ hybridization,western blotting, and the reversed transcriptive polymerase chain reaction(RT-PCR).Results: Compared to control group,the score of stereotyped behavior and CPP of four dependent groups had significant difference(P＜0.05).There were positive expression in all six regions with DAT,DRD1,DRD2,and SERT.Compared to the same cerebral region in different groups,the expression of DAT,DRD1,DRD2,and SEPT were difference(P＜0.05).At frontal cortex,the DAT decreased in 1 week,increased in 2 weeks and continuous to 4 weeks,then decreased in 8 weeks.There was significant differnce that compared cotrol group with 1,2,8 weeks group,4 weeks with 8 weeks group(P＜0.05 ).The DRD1 decreased in 1 week,increased in 2 weeks and continuous to 4 weeks,then decreased in 8 weeks.There was significant differnce that compared cotrol group with 1,4 weeks group.The DRD2 were increased in 1 week,then decreased in 2 weeks and continuous to 4 weeks,then increased again in 8 weeks. There was significant diffemce that compared cotrol group with 1,2,8 weeks group, 1 week with 4 weeks group,4 weeks with 8 weeks group(P＜0.05).The SERT decreased in 1 week and continuous to 2 weeks,then increased in 4 weeks,decresed again in 8 weeks.There was significant differnce that compared cotrol group with 1,2 weeks group(P＜0.05).At nucleus accumbens septum,the DAT decreased in 1 week and continuous to 2 weeks,increased in 4 weeks,then decreased again in 8 weeks. There was significant differnce that compared cotrol group with 1,2,8 weeks group, 1 week with 4 weeks group,2week with 4 weeks and 8 weeks group(P＜0.05).The DRD1 increased from 1 week to 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 increased in 1 week and continuous to 2 weeks,then decreased in 4 weeks and increased again in 8 weeks. There was significant diffemce that compared cotrol group with 1,2,8 weeks group, 4 weeks with 8 weeks group(P＜0.05).The SERT decreased in 1 week and continuous to 2 weeks,then increased in 4 weeks,decreased again in 8 weeks.There was significant differnce that compared cotrol group with 1,2 weeks group,1 week with 4 weeks and 8 weeks group,2 week with 4 weeks and 8 weeks group(P＜0.05). At striatum,the DAT decreased in 1 week,then increased in 2 weeks and continuous to 4 weeks,decreased again in 8 weeks.There was significant differnce that compared cotrol group with 1,2,8 weeks group(P＜0.05).The DRD1 decreased from 1 week to 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 increased in 1 week and continuous to 2 weeks,then decreased till 8 weeks.There was significant differnce that compared cotrol group with 1,2 weeks group(P＜0.05).The SERT decreased from 1 week to 2 weeks,then increased in 4 weeks and decreased again in 8 weeks.There was significant differnce that compared cotrol group with 2,4,8 weeks group,1 week with 2 weeks group(P＜0.05).At hippocampus,the DAT and DRD1 increased in 1 week,then decreased from 2 weeks to 4 weeks,increased again in 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 decreased in 1 week,then increased from 2 weeks to 8 weeks.There was significant differnce that compared cotrol group with 1,2,4,8 weeks group(P＜0.05 ).The SERT decreased from 1 week to 2 weeks,increased in 4 weeks and decreased in 8 weeks. There was significant differnce that compared cotrol group with 2 weeks group,1 week group with 2 weeks group,2 weeks with 1,4 weeks group(P＜0.05).At ventral tegmental area,the DAT increased from 1 week to 8 weeks.There was significant differnce that compared cotrol group with 4,8 weeks group(P＜0.05).The DRD1 increased from 1 week to 4 weeks,then decreased in 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 increased from 1 week to 2 weeks,then decreased from 4 weeks to 8 weeks. There was significant differnce that compared cotrol group with 2 weeks group(P＜0.05 ).The SERT decreased in 1 week,then increased in 2 weeks and decreased from 4 weeks to 8 weeks again.There was significant differnce that compared cotrol group with 1,4,8 weeks group,2 weeks group with 4 weeks and 8 weeks group(P＜0.05). At substantia nigra,the DAT decreased in 1 week,then increased in 2 weeks, decreased from 4 to 8 weeks.There was significant differnce that compared 2 weeks group with 4,8 weeks group(P＜0.05).The DRD1 increased in 1 week and decreased in 2 weeks,then increased from 4 to 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 increased in 1 week and decreased from 2 to 4 weeks,then increased again in 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The SERT decreased from 1 to 2 weeks,increased in 4 weeks and decreased again in 8 weeks.There was significant differnce that compared cotrol group with 1,2,4,8 weeks group(P＜0.05).Compared to the six different regions in same experiment group,the DAT,DRD1,DRD2,and SERT also had different changes,and had significant difference at several cerebral regions(P＜0.05).Conclusion:1.the rat model of MA dependence can be established succussfully that use the method of multi-administer MA and comfirm with experiment of CPP.2.at frontal cortex, nucleus accumbens septum,striatum,hippocampus,ventral tegrnental area,and substantia nigra,the expression of DAT,DRD1,DRD2,and SERT had significant diffenence,which related to the different cerebral regions and the time course of administered MA.The changes of DAT,DRD1,DRD2,and SERT may play a crucial role in MA dependece.
在伏隔核,DAT依赖一周组明显下降并持续到两周,四周时又明显回升,到八周时又出现轻度下降。对照组和一周组、两周组、八周组比较、一周组和四周组比较、两周组和四周组、八周组比较有统计学意义(P＜0.05)。DRD1依赖一周组至八周均表现为升高,但组间两两比较均无统计学差异。DRD2依赖一周组明显升高并持续到两周,四周时开始下降,八周时又明显升高。对照组和一周组、两周组、八周组比较、四周组和八周组比较有统计学意义(P＜0.05)。SERT依赖一周组明显下降,持续至两周,四周时明显升高,八周时又稍下降。对照组和一周组、两周组比较、一周组和四周组、八周组比较、两周组和四周组、八周组比较有统计学意义(P＜0.05)。在纹状体,DAT依赖一周组明显下降,两周组轻度回升并持续到四周,八周组出现轻度下降。对照组和一周组、两周组、八周组比较有统计学意义(P＜0.05)。DRD1依赖一周至八周,均呈下降趋势,但组间两两比较均无统计学差异。DRD2依赖一周组明显升高并持续到两周,四周组下降并持续到八周。对照组、一周组和两周组比较有统计学意义(P＜0.05)。SERT依赖一周后下降并持续至两周,四周时则开始升高,到八周时又再次下降。对照组和两周组、四周组、八周组比较、一周组和两周组比较有统计学意义(P＜0.05)。在海马,DAT依赖一周组升高,到两周时下降并持续到四周,八周时又轻度升高。但组间两两比较均无统计学差异。DRD1依赖一周组升高,两周时下降并持续到四周,到八周时又回升,但组间两两比较均无统计学差异。DRD2依赖一周组明显下降,两周时逐渐回升并持续至八周,对照组和一周组、两周组、四周组、八周组比较均有统计学意义(P＜0.05)。SERT依赖一周组下降并持续至两周,四周时开始升高,到八周时又再次下降。对照组、一周组和两周组比较、两周组和一周组、四周组比较有统计学意义(P＜0.05)。在中脑腹侧被盖,DAT依赖一周到八周均升高,对照组与四周组、八周组有统计学差异(P＜0.05)。DRD1依赖一周组升高并持续到两周、四周,到八周时稍下降,组间两两比较均无统计学差异。DRD2依赖一周组明显升高并持续到两周,四周时开始下降并持续到八周。对照组和两周组比较有统计学意义(P＜0.05)。SERT依赖一周组下降,至两周时明显回升,四周时又明显下降并持续至八周。对照组和一周组、四周组、八周组比较、两周组和四周组、八周组比较有统计学意义(P＜0.05)。在黑质,DAT依赖一周组下降,两周组明显升高,四周时明显下降并持续至八周,两周组与四周组、八周组比较有统计学意义(P＜0.05)。DRD1依赖一周组升高,两周时稍下降,从四周开始回升并持续至八周,但组间两两比较均无统计学差异。DRD2依赖一周组升高,两周时开始下降并持续至四周,八周时又逐渐回升,但组间两两比较均无统计学差异。SERT依赖一周组下降并持续至两周,四周时明显回升,八周时又稍下降。对照组和一周组、两周组、四周组、八周组比较有统计学意义(P＜0.05)。在同一实验组的不同脑区,DAT、DRD1、DRD2、SERT表达呈现不同的变化趋势,部分脑区之间表达具有统计学差异(P＜0.05)。结论:1.采用多次腹腔注射甲基苯丙胺,结合条件性位置偏爱实验的方法成功建立甲基苯丙胺依赖大鼠模型;2.在额叶皮质、伏隔核、纹状体、海马、中脑腹侧被盖、黑质六个脑区多巴胺转运体、多巴胺受体D1、多巴胺受体D2、五羟色胺转运体的表达存在明显变化,并且不同脑区之间和不同依赖时间段之间的表达存在一定差异,多巴胺转运体、多巴胺受体D1、多巴胺受体D2、五羟色胺转运体的表达变化与甲基苯丙胺依赖机制有密切关系。
Objective:To establish a rat model of methamphetamine(MA)dependence,then detect the expression of dopamine transporter(DAT),dopamine receptor D 1(DRD1), dopamine receptor D2(DRD2),and serotonin transporter(SERT)in six cerebral regions which related to MA dependence.Then investigate the correlation between the expression of DAT,DRD1,DRD2 and SEPT with the mechanism of MA dependence.Methods:The rats were devided into five groups which were control group,1 week group,2 weeks group,4 weeks group,and 8 weeks group of MA dependence.The models of diffenrent periods of administered MA(ip,10mg.kg-1 per day)were established.Then observe the stereotyped behavior and do experiment of conditioned position preference(CPP)to confirm the models were successfully esablished.The animals were sacrificed,the brain tissues of the prefrontal cortex, nucleus accumbens septum,striatum,hippocampus,ventral tegmental area,and substantia nigra were collected to detect the expression of DAT,DRD1,DRD1,SERT with the methods of immunohistochemistry,in situ hybridization,western blotting, and the reversed transcriptive polymerase chain reaction(RT-PCR).Results: Compared to control group,the score of stereotyped behavior and CPP of four dependent groups had significant difference(P＜0.05).There were positive expression in all six regions with DAT,DRD1,DRD2,and SERT.Compared to the same cerebral region in different groups,the expression of DAT,DRD1,DRD2,and SEPT were difference(P＜0.05).At frontal cortex,the DAT decreased in 1 week,increased in 2 weeks and continuous to 4 weeks,then decreased in 8 weeks.There was significant differnce that compared cotrol group with 1,2,8 weeks group,4 weeks with 8 weeks group(P＜0.05 ).The DRD1 decreased in 1 week,increased in 2 weeks and continuous to 4 weeks,then decreased in 8 weeks.There was significant differnce that compared cotrol group with 1,4 weeks group.The DRD2 were increased in 1 week,then decreased in 2 weeks and continuous to 4 weeks,then increased again in 8 weeks. There was significant diffemce that compared cotrol group with 1,2,8 weeks group, 1 week with 4 weeks group,4 weeks with 8 weeks group(P＜0.05).The SERT decreased in 1 week and continuous to 2 weeks,then increased in 4 weeks,decresed again in 8 weeks.There was significant differnce that compared cotrol group with 1,2 weeks group(P＜0.05).At nucleus accumbens septum,the DAT decreased in 1 week and continuous to 2 weeks,increased in 4 weeks,then decreased again in 8 weeks. There was significant differnce that compared cotrol group with 1,2,8 weeks group, 1 week with 4 weeks group,2week with 4 weeks and 8 weeks group(P＜0.05).The DRD1 increased from 1 week to 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 increased in 1 week and continuous to 2 weeks,then decreased in 4 weeks and increased again in 8 weeks. There was significant diffemce that compared cotrol group with 1,2,8 weeks group, 4 weeks with 8 weeks group(P＜0.05).The SERT decreased in 1 week and continuous to 2 weeks,then increased in 4 weeks,decreased again in 8 weeks.There was significant differnce that compared cotrol group with 1,2 weeks group,1 week with 4 weeks and 8 weeks group,2 week with 4 weeks and 8 weeks group(P＜0.05). At striatum,the DAT decreased in 1 week,then increased in 2 weeks and continuous to 4 weeks,decreased again in 8 weeks.There was significant differnce that compared cotrol group with 1,2,8 weeks group(P＜0.05).The DRD1 decreased from 1 week to 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 increased in 1 week and continuous to 2 weeks,then decreased till 8 weeks.There was significant differnce that compared cotrol group with 1,2 weeks group(P＜0.05).The SERT decreased from 1 week to 2 weeks,then increased in 4 weeks and decreased again in 8 weeks.There was significant differnce that compared cotrol group with 2,4,8 weeks group,1 week with 2 weeks group(P＜0.05).At hippocampus,the DAT and DRD1 increased in 1 week,then decreased from 2 weeks to 4 weeks,increased again in 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 decreased in 1 week,then increased from 2 weeks to 8 weeks.There was significant differnce that compared cotrol group with 1,2,4,8 weeks group(P＜0.05 ).The SERT decreased from 1 week to 2 weeks,increased in 4 weeks and decreased in 8 weeks. There was significant differnce that compared cotrol group with 2 weeks group,1 week group with 2 weeks group,2 weeks with 1,4 weeks group(P＜0.05).At ventral tegmental area,the DAT increased from 1 week to 8 weeks.There was significant differnce that compared cotrol group with 4,8 weeks group(P＜0.05).The DRD1 increased from 1 week to 4 weeks,then decreased in 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 increased from 1 week to 2 weeks,then decreased from 4 weeks to 8 weeks. There was significant differnce that compared cotrol group with 2 weeks group(P＜0.05 ).The SERT decreased in 1 week,then increased in 2 weeks and decreased from 4 weeks to 8 weeks again.There was significant differnce that compared cotrol group with 1,4,8 weeks group,2 weeks group with 4 weeks and 8 weeks group(P＜0.05). At substantia nigra,the DAT decreased in 1 week,then increased in 2 weeks, decreased from 4 to 8 weeks.There was significant differnce that compared 2 weeks group with 4,8 weeks group(P＜0.05).The DRD1 increased in 1 week and decreased in 2 weeks,then increased from 4 to 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The DRD2 increased in 1 week and decreased from 2 to 4 weeks,then increased again in 8 weeks.There was no significant differnce that compared cotrol group with four dependent groups.The SERT decreased from 1 to 2 weeks,increased in 4 weeks and decreased again in 8 weeks.There was significant differnce that compared cotrol group with 1,2,4,8 weeks group(P＜0.05).Compared to the six different regions in same experiment group,the DAT,DRD1,DRD2,and SERT also had different changes,and had significant difference at several cerebral regions(P＜0.05).Conclusion:1.the rat model of MA dependence can be established succussfully that use the method of multi-administer MA and comfirm with experiment of CPP.2.at frontal cortex, nucleus accumbens septum,striatum,hippocampus,ventral tegrnental area,and substantia nigra,the expression of DAT,DRD1,DRD2,and SERT had significant diffenence,which related to the different cerebral regions and the time course of administered MA.The changes of DAT,DRD1,DRD2,and SERT may play a crucial role in MA dependece.
引文
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