Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025, USA.
Eur J Neurosci. 2019 Mar;49(6):859-868. doi: 10.1111/ejn.14048. Epub 2018 Jul 21.
L-dopa induced dyskinesias (LIDs) are a disabling motor complication of L-dopa therapy for Parkinson's disease (PD) management. Treatment options remain limited and the underlying network mechanisms remain unclear due to a complex pathophysiology. What is well-known, however, is that aberrant striatal signaling plays a key role in LIDs development. Here, we discuss the specific contribution of striatal cholinergic interneurons (ChIs) and GABAergic medium spiny projection neurons (MSNs) with a particular focus on how cholinergic signaling may integrate multiple striatal systems to modulate LIDs expression. Enhanced ChI transmission, altered MSN activity and the associated abnormal downstream signaling responses that arise with nigrostriatal damage are well known to contribute to LIDs development. In fact, enhancing M4 muscarinic receptor activity, a receptor favorably expressed on D1 dopamine receptor-expressing MSNs dampens their activity to attenuate LIDs. Likewise, ChI activation via thalamostriatal neurons is shown to interrupt cortical signaling to enhance D2 dopamine receptor-expressing MSN activity via M1 muscarinic receptors, which may interrupt ongoing motor activity. Notably, numerous preclinical studies also show that reducing nicotinic cholinergic receptor activity decreases LIDs. Taken together, these studies indicate the importance of cholinergic control of striatal neuronal activity and point to muscarinic and nicotinic receptors as significant pharmacological targets for alleviating LIDs in PD patients.
左旋多巴诱导的运动障碍（LIDs）是左旋多巴治疗帕金森病（PD）管理的一种致残性运动并发症。由于复杂的病理生理学，治疗选择仍然有限，潜在的网络机制仍不清楚。然而，众所周知的是，纹状体信号异常在 LIDs 的发展中起着关键作用。在这里，我们讨论了纹状体胆碱能中间神经元（ChIs）和 GABA 能中间神经元（MSNs）的特定贡献，特别关注胆碱能信号如何整合多个纹状体系统来调节 LIDs 的表达。增强 ChI 传递、改变 MSN 活性以及与黑质纹状体损伤相关的异常下游信号反应，这些都被认为是 LIDs 发展的原因。事实上，增强 M4 毒蕈碱受体活性，这种受体在表达 D1 多巴胺受体的 MSN 上表达良好，可抑制其活性以减轻 LIDs。同样，通过丘脑纹状体神经元激活 ChI 被证明可以中断皮质信号，通过 M1 毒蕈碱受体增强表达 D2 多巴胺受体的 MSN 活性，从而中断正在进行的运动活动。值得注意的是，许多临床前研究还表明，降低烟碱型胆碱能受体活性可减少 LIDs。综上所述，这些研究表明了纹状体神经元活动的胆碱能控制的重要性，并指出毒蕈碱和烟碱受体是缓解 PD 患者 LIDs 的重要药理学靶点。
