Pharmacological analysis of the functional ontogeny of the nigrostriatal dopaminergic neurons
Pharmacological analysis of the functional ontogeny of the nigrostriatal dopaminergic neurons
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黑质纹状体多巴胺能神经元功能个体发育的药理学分析
DOI：
10.1016/0006-8993(79)90403-7
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发表时间：
1979
期刊：
影响因子：
2.9
通讯作者：
P. Hoffmann
中科院分区：
文献类型：
--
作者：
J. Cheronis;L. Erinoff;A. Heller;P. Hoffmann
多巴胺能黑质纹状体投射的功能发展进行了研究，确定的年龄，这些神经元的生理或药理学操作的生化反应是类似的成年神经元。在成年和8或10日龄大鼠中，横断该通路可急性升高纹状体多巴胺，但在4或6日龄大鼠中则不然。这种轴突切断诱导的纹状体多巴胺增加被认为是多巴胺能末梢对脉冲交通停止的反应，并且继发于多巴胺释放减少和酪氨酸羟化酶激活导致的多巴胺合成伴随增加。因此，这种对轴突切断的反应作为（1）通路中脉冲交通的存在和（2）酪氨酸羟化酶响应于这种脉冲交通的减少而被激活的能力的指示。酪氨酸羟化酶活性的体内估计显示，轴突切断在10天激活该酶，但在4天不激活，而γ-羟基丁酸酯在两个年龄段都有效。该酶在4天可以被γ-羟基丁酸酯激活的事实表明，在该年龄段轴突切断缺乏作用是由于系统中没有脉冲交通。这一结论得到了以下发现的支持：4日龄时，AMT诱导的纹状体多巴胺耗竭与冲动传导无关，因为该通路的横断对多巴胺丢失率没有影响，而这种横断在10日龄时阻断了AMT诱导的耗竭。然而，尽管在4日龄时没有神经元活动，但这些神经元能够产生和进行脉冲交通，因为4日龄和10日龄大鼠在用氟哌啶醇处理时均显示纹状体二羟基苯乙酸（DOPAC）水平增加，表明多巴胺释放增加; DOPAC的这种增加依赖于完整的通路。鉴于这些数据，对6日龄后轴突切断反应的突然发展的最简洁的解释是，发生了生理上启动冲动交通的事件。这一事件可能是传入神经元输入到黑质纹状体投射的细胞体的激活。
Functional development of the dopaminergic nigrostriatal projection was studied by determining the age at which the biochemical responses of these neurons to physical or pharmacological manipulation are similar to those of adult neurons. Transection of the pathway acutely elevates striatal dopamine in adult and 8- or 10-day-old rats, but not in the 4- or 6-day-old animal. This axotomy-induced increase in striatal dopamine is believed to be a response of the dopaminergic terminals to cessation of impulse traffic and is secondary to a decrease in dopamine release and a concomitant increase in dopamine synthesis resulting from tyrosine hydroxylase activation. Therefore, this response to axotomy acts as an indicator of (1) the presence of impulse traffic in the pathway, and (2) the ability of tyrosine hydroxylase to be activated in response to a reduction in such impulse traffic. In vivo estimation of tyrosine hydroxylase activity showed that axotomy activates the enzyme at 10 days, but not at 4 days, whereas γ-hydroxybutyrate is effective at both ages, The fact that the enzyme can be activated by γ-hydroxybutyrate at 4 days indicates that the lack of effect of axotomy at this age is due to the absence of impulse traffic in the system. This conclusion is supported by the finding that the AMT-induced depletion of striatal dopamine is not related to impulse conduction at 4 days since transection of the pathway has no effect on the rate of dopamine loss whereas such transection blocks the AMT-induced depletion at 10 days of age. Nevertheless, despite the absence of neuronal activity at 4 days of age, these neurons are capable of generating and conducting impulse traffic since both 4- and 10-day-old rats showed increased striatal dihydroxyphenylacetic acid (DOPAC) levels when treated with haloperidol indicating increased dopamine release; such increases in DOPAC being dependent on an intact pathway. Given this data, the most parsimonious explanation for the abrupt development of the response to axotomy after the 6th day of age is that an event occurs which physiologically initiates impulse traffic. This event may be activation of afferent neuronal inputs to the cell bodies of the nigrostriatal projection.