Department of Pharmacology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States.
Front Neural Circuits. 2018 Jul 30;12:57. doi: 10.3389/fncir.2018.00057. eCollection 2018.
Dopamine (DA) profoundly stimulates motor function as demonstrated by the hypokinetic motor symptoms in Parkinson's disease (PD) and by the hyperkinetic motor side effects during dopaminergic treatment of PD. Dopamine (DA) receptor-bypassing, optogenetics- and chemogenetics-induced spike firing of striatal DA D1 receptor (D1R)-expressing, direct pathway medium spiny neurons (dSPNs or dMSNs) promotes movements. However, the endogenous D1R-mediated effects, let alone those of DA replacement, on dSPN spike activity in freely-moving animals is not established. Here we show that using transcription factor Pitx3 null mutant (Pitx3Null) mice as a model for severe and consistent DA denervation in the dorsal striatum in Parkinson's disease, antidromically identified striatonigral neurons (D1R-expressing dSPNs) had a lower baseline spike firing rate than that in DA-intact normal mice, and these neurons increased their spike firing more strongly in Pitx3Null mice than in WT mice in response to injection of L-dopa or the D1R agonist, SKF81297; the increase in spike firing temporally coincided with the motor-stimulating effects of L-dopa and SKF81297. Taken together, these results provide the first evidence from freely moving animals that in parkinsonian striatum, identified behavior-promoting dSPNs become hyperactive upon the administration of L-dopa or a D1 agonist, likely contributing to the profound dopaminergic motor stimulation in parkinsonian animals and PD patients.
多巴胺（DA）深刻地刺激运动功能，这在帕金森病（PD）的运动迟缓症状和 PD 多巴胺能治疗的运动过度副作用中得到了证明。纹状体 DA D1 受体（D1R）表达的直接通路中间神经元（dSPN 或 dMSN）的多巴胺受体旁路、光遗传学和化学遗传学诱导的尖峰放电促进运动。然而，在自由活动的动物中，内源性 D1R 介导的作用，更不用说 DA 替代的作用，对 dSPN 尖峰活动的影响尚未确定。在这里，我们使用转录因子 Pitx3 缺失突变（Pitx3Null）小鼠作为帕金森病背侧纹状体严重和持续 DA 去神经支配的模型，发现逆行鉴定的纹状体苍白球神经元（D1R 表达的 dSPN）的基线尖峰放电率低于 DA 完整的正常小鼠，并且这些神经元对 L-多巴或 D1R 激动剂 SKF81297 的反应更强；尖峰放电的增加与 L-多巴和 SKF81297 的运动刺激作用在时间上是一致的。综上所述，这些结果首次从自由活动的动物中提供了证据，即在帕金森病纹状体中，被识别为促进行为的 dSPN 在给予 L-多巴或 D1 激动剂后变得过度活跃，这可能有助于帕金森病动物和 PD 患者的深刻多巴胺运动刺激。
