Striatal But Not Extrastriatal Dopamine Receptors Are Critical to Dopaminergic Motor Stimulation
Striatal But Not Extrastriatal Dopamine Receptors Are Critical to Dopaminergic Motor Stimulation
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DOI：
10.3389/fphar.2017.00935
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发表时间：
2017-12-21
影响因子：
5.6
通讯作者：
Zhou, Fu-Ming
中科院分区：
文献类型：
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作者：
Wang, Yuhan;Zhou, Fu-Ming
多巴胺（DA）是包括人类在内的脊椎动物的运动功能所必需的。纹状体是一个关键的运动控制中心，接受密集的DA神经支配，并表达高水平的DA D1受体（D1 Rs）和D2受体（D2 Rs）。参与运动功能的其他脑区，如苍白球外段（GPe）和黑质网状部（SNr）以及运动皮质（MC）也接受DA神经支配并表达DA受体。因此，纹状体和纹状体外DA系统对运动功能的相对贡献一直是理解运动控制回路的功能操作以及治疗靶向的重要问题。我们现在已经在实验中解决了这个问题，在转录因子Pitx 3无效突变（Pitx 3bu）小鼠，有一个自体和帕金森样纹状体DA去神经支配，因此超敏感的运动反应DA刺激。使用DA激动剂单侧微注射诱导的旋转作为运动刺激的可靠读出，我们的结果表明，L-dopa微注射到背侧纹状体（DS）诱导的旋转比L-dopa微注射到GPe和SNr诱导的旋转多5-10倍，而L-dopa微注射到初级MC诱导的旋转次数最少。此外，我们的研究结果表明，单独微量注射的D1 R样激动剂SKF 81297和D2 R样激动剂罗匹尼罗到DS中，每个只引起适度的旋转数，而同时注射的两种激动剂引发更多的旋转比这两种激动剂分别引起的旋转的总和，表明D1 R-D2 R协同作用。这些结果表明，纹状体，而不是GPe，SNr或MC，是D1 Rs和D2 Rs协同刺激运动功能在左旋多巴治疗帕金森病（PD）的主要网站。我们的研究结果还预测，非选择性，广谱DA激动剂激活D1 R和D2 R是更有效的抗PD药物比目前的D2 R激动剂。
Dopamine (DA) is required for motor function in vertebrate animals including humans. The striatum, a key motor control center, receives a dense DA innervation and express high levels of DA D1 receptors (D1Rs) and D2 receptors (D2Rs). Other brain areas involved in motor function such as the globus pallidus external segment (GPe) and the substantia nigra pars reticulata (SNr) and the motor cortex (MC) also receive DA innervation and express DA receptors. Thus, the relative contribution of the striatal and extrastriatal DA systems to the motor function has been an important question critical for understanding the functional operation of the motor control circuits and also for therapeutic targeting. We have now experimentally addressed this question in the transcription factor Pitx3 null mutant (Pitx3Null) mice that have an autogenic and parkinsonian-like striatal DA denervation and hence supersensitive motor response to DA stimulation. Using DA agonist unilateral microinjection-induced rotation as a reliable readout of motor stimulation, our results show that L-dopa microinjection into the dorsal striatum (DS) induced 5-10 times more rotations than that induced by L-dopa microinjection into GPe and SNr, while L-dopa microinjection into the primary MC induced the least number of rotations. Furthermore, our results show that separate microinjection of the D1R-like agonist SKF81297 and the D2R-like agonist ropinirole into the DS each induced only modest numbers of rotation, whereas concurrent injection of the two agonists triggered more rotations than the sum of the rotations induced by each of these two agonists separately, indicating D1R-D2R synergy. These results suggest that the striatum, not GPe, SNr or MC, is the primary site for D1Rs and D2Rs to synergistically stimulate motor function in L-dopa treatment of Parkinson's disease (PD). Our results also predict that non-selective, broad spectrum DA agonists activating both D1Rs and D2Rs are more efficacious anti-PD drugs than the current D2R agonists.