Universidad de Buenos Aires, CONICET, Instituto de Fisiología y Biofísica (IFIBIO) Bernardo Houssay, Grupo de Neurociencia de Sistemas, 2155 Paraguay Street, Buenos Aires 1121, Argentina.
Universidad de Buenos Aires, CONICET, Instituto de Fisiología y Biofísica (IFIBIO) Bernardo Houssay, Grupo de Neurociencia de Sistemas, 2155 Paraguay Street, Buenos Aires 1121, Argentina.
Neuroscience. 2021 Jul 15;467:201-217. doi: 10.1016/j.neuroscience.2021.05.026. Epub 2021 May 25.
Before the advent of L-DOPA, the gold standard symptomatic therapy for Parkinson's disease (PD), anticholinergic drugs (muscarinic receptor antagonists) were the preferred antiparkinsonian therapy, but their unwanted side effects associated with impaired extrastriatal cholinergic function limited their clinical utility. Since most patients treated with L-DOPA also develop unwanted side effects such as L-DOPA-induced dyskinesia (LID), better therapies are needed. Recent studies in animal models demonstrate that optogenetic and chemogenetic manipulation of striatal cholinergic interneurons (SCIN), the main source of striatal acetylcholine, modulate parkinsonism and LID, suggesting that restoring SCIN function might serve as a therapeutic option that avoids extrastriatal anticholinergics' side effects. However, it is still unclear how the altered SCIN activity in PD and LID affects the striatal circuit, whereas the mechanisms of action of anticholinergic drugs are still not fully understood. Recent animal model studies showing that SCINs undergo profound changes in their tonic discharge pattern after chronic L-DOPA administration call for a reexamination of classical views of how SCINs contribute to PD symptoms and LID. Here, we review the recent advances on the circuit implications of aberrant striatal cholinergic signaling in PD and LID in an effort to provide a comprehensive framework to understand the effects of anticholinergic drugs and with the aim of shedding light into future perspectives of cholinergic circuit-based therapies.
在左旋多巴（L-DOPA）问世之前，L-DOPA 是治疗帕金森病（PD）的金标准对症治疗药物，而抗胆碱能药物（毒蕈碱受体拮抗剂）是首选的抗帕金森药物，但它们会损害纹状体外的胆碱能功能，从而产生不良的副作用，限制了其临床应用。由于大多数接受 L-DOPA 治疗的患者也会出现不良副作用，如 L-DOPA 诱导的运动障碍（LID），因此需要更好的治疗方法。最近的动物模型研究表明，纹状体内胆能中间神经元（SCIN）的光遗传学和化学遗传学操作，即纹状体内乙酰胆碱的主要来源，可以调节帕金森病和 LID，这表明恢复 SCIN 功能可能是一种避免纹状体外抗胆碱能药物副作用的治疗选择。然而，目前尚不清楚 PD 和 LID 中改变的 SCIN 活性如何影响纹状体回路，而抗胆碱能药物的作用机制仍不完全清楚。最近的动物模型研究表明，慢性 L-DOPA 给药后，SCIN 的紧张性放电模式发生了深刻变化，这就需要重新审视 SCIN 如何导致 PD 症状和 LID 的经典观点。在这里，我们综述了纹状体胆碱能信号异常在 PD 和 LID 中的回路意义的最新进展，努力为理解抗胆碱能药物的作用提供一个全面的框架，并为基于胆碱能回路的治疗方法提供未来的研究方向。
