Li Hongxia, Chen Ziluo, Tan Yuyan, Luo Huoqing, Lu Chen, Gao Chao, Shen Xin, Cai Fang, Hu Ji, Chen Shengdi
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Lab for Translational Research of Neurodegenerative Diseases, Institute of Immunochemistry, ShanghaiTech University, Shanghai, China.
Cell Biosci. 2024 Dec 3;14(1):146. doi: 10.1186/s13578-024-01328-z.
L-DOPA has been considered the first-line therapy for treating Parkinson's disease (PD) via restoring striatal dopamine (DA) to normalize the activity of local spiny projection neurons (SPNs) in the direct (dSPNs) pathway and the indirect (iSPNs) pathway. While the changes in striatal acetylcholine (ACh) induced by increasing DA have been extensively discussed, their validity remains controversial. Inhibition of striatal cholinergic signaling attenuates PD motor deficits. Interestingly, enhancing striatal ACh triggers local DA release, suggesting the pro-kinetic effects of ACh in movement control. Here, we investigated the in-vivo dynamics of ACh in the dorsolateral striatum (DLS) of the 6-OHDA-lesioned mouse model after L-DOPA administration, as well as its underlying mechanism, and to explore its modulatory role and mechanism in parkinsonian symptoms.
Using in vivo fiber photometry recordings with genetically encoded fluorescent DA or ACh indicator, we found L-DOPA selectively decreased DLS ACh levels in parkinsonian conditions. DA inhibited ACh release via dopamine D2 receptors and dSPNs-mediated activation of type-A γ-aminobutyric acid receptors on cholinergic interneurons. Restoring DLS ACh levels during L-DOPA treatment induced additional DA release by activating nicotinic acetylcholine receptors, thereby promoting the activity of dSPNs and iSPNs. Enhancing DLS ACh facilitated L-DOPA-induced turning behavior but not dyskinesia in parkinsonian mice.
Our results demonstrated that enhancing striatal ACh facilitated the effect of L-DOPA by modulating DA tone. It may challenge the classical hypothesis of a purely competitive interaction between dopaminergic and cholinergic neuromodulation in improving PD motor deficits. Modulating ACh levels within the dopaminergic system may improve striatal DA availability in PD patients.
左旋多巴一直被认为是治疗帕金森病（PD）的一线疗法，通过恢复纹状体多巴胺（DA）水平，使直接（dSPNs）通路和间接（iSPNs）通路中的局部棘状投射神经元（SPNs）活动恢复正常。虽然多巴胺增加所诱导的纹状体乙酰胆碱（ACh）变化已被广泛讨论，但其有效性仍存在争议。抑制纹状体胆碱能信号可减轻PD运动缺陷。有趣的是，增强纹状体ACh会触发局部DA释放，提示ACh在运动控制中具有促运动作用。在此，我们研究了左旋多巴给药后6-羟基多巴胺（6-OHDA）损伤小鼠模型背外侧纹状体（DLS）中ACh的体内动态变化及其潜在机制，并探讨其对帕金森症状的调节作用和机制。
使用基因编码的荧光DA或ACh指示剂进行体内光纤光度记录，我们发现左旋多巴在帕金森病状态下选择性降低了DLS中的ACh水平。DA通过多巴胺D2受体和dSPNs介导的胆碱能中间神经元上A型γ-氨基丁酸受体的激活来抑制ACh释放。在左旋多巴治疗期间恢复DLS中的ACh水平，可通过激活烟碱型乙酰胆碱受体诱导额外的DA释放，从而促进dSPNs和iSPNs的活性。增强DLS中的ACh可促进左旋多巴诱导的帕金森病小鼠的转向行为，但不会促进异动症。
我们的结果表明，增强纹状体ACh通过调节DA水平促进了左旋多巴的作用。这可能挑战了多巴胺能和胆碱能神经调节在改善PD运动缺陷方面纯粹竞争性相互作用的经典假说。调节多巴胺能系统内的ACh水平可能改善PD患者纹状体DA的可用性。
