Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
Cell and Molecular Biology Program, Michigan State University, East Lansing, MI, USA.
Acta Neuropathol Commun. 2019 Jan 15;7(1):8. doi: 10.1186/s40478-018-0653-7.
Levodopa-induced dyskinesias (LID) are a prevalent side effect of chronic treatment with levodopa (L-DOPA) for the motor symptoms of Parkinson's disease (PD). It has long been hypothesized that serotonergic neurons of the dorsal raphe nucleus (DRN) are capable of L-DOPA uptake and dysregulated release of dopamine (DA), and that this "false neurotransmission" phenomenon is a main contributor to LID development. Indeed, many preclinical studies have demonstrated LID management with serotonin receptor agonist treatment, but unfortunately, promising preclinical data has not been translated in large-scale clinical trials. Importantly, while there is an abundance of convincing clinical and preclinical evidence supporting a role of maladaptive serotonergic neurotransmission in LID expression, there is no direct evidence that dysregulated DA release from serotonergic neurons impacts LID formation. In this study, we ectopically expressed the DA autoreceptor D2R (or GFP) in the DRN of 6-hydroxydopamine (6-OHDA) lesioned rats. No negative impact on the therapeutic efficacy of L-DOPA was seen with rAAV-D2R therapy. However, D2R treated animals, when subjected to a LID-inducing dose regimen of L-DOPA, remained completely resistant to LID, even at high doses. Moreover, the same subjects remained resistant to LID formation when treated with direct DA receptor agonists, suggesting D2R activity in the DRN blocked dyskinesogenic L-DOPA priming of striatal neurons. In vivo microdialysis confirmed that DA efflux in the striatum was reduced with rAAV-D2R treatment, providing explicit evidence that abnormal DA release from DRN neurons can affect LID. This is the first direct evidence of dopaminergic neurotransmission in DRN neurons and its modulation with rAAV-D2R gene therapy confirms the serotonin hypothesis in LID, demonstrating that regulation of serotonergic neurons achieved with a gene therapy approach offers a novel and potent antidyskinetic therapy.
左旋多巴诱导的运动障碍（LID）是慢性左旋多巴（L-DOPA）治疗帕金森病（PD）运动症状的常见副作用。长期以来，人们一直假设背侧中缝核（DRN）的 5-羟色胺能神经元能够摄取 L-DOPA 并失调地释放多巴胺（DA），而这种“假性神经传递”现象是 LID 发展的主要原因。事实上，许多临床前研究已经证明了使用 5-羟色胺受体激动剂治疗 LID，但不幸的是，有前景的临床前数据并没有在大规模临床试验中得到转化。重要的是，虽然有大量令人信服的临床和临床前证据支持适应性 5-羟色胺能神经传递在 LID 表达中的作用，但没有直接证据表明来自 5-羟色胺能神经元的失调 DA 释放会影响 LID 的形成。在这项研究中，我们在 6-羟多巴胺（6-OHDA）损伤大鼠的 DRN 中异位表达了 DA 自身受体 D2R（或 GFP）。rAAV-D2R 治疗对 L-DOPA 的治疗效果没有产生负面影响。然而，用 D2R 处理的动物，当接受 LID 诱导剂量方案的 L-DOPA 治疗时，即使在高剂量下，也完全对 LID 有抵抗力。此外，当用直接 DA 受体激动剂治疗时，同一受试者仍然对 LID 形成有抵抗力，这表明 DRN 中的 D2R 活性阻止了纹状体神经元产生运动障碍的 LID 引发。体内微透析证实，rAAV-D2R 治疗可降低纹状体中的 DA 外排，这提供了明确的证据，表明来自 DRN 神经元的异常 DA 释放会影响 LID。这是 DRN 神经元中多巴胺能神经传递的第一个直接证据，rAAV-D2R 基因治疗对其的调节证实了 LID 中的 5-羟色胺假说，表明通过基因治疗方法调节 5-羟色胺能神经元为提供了一种新型有效的抗运动障碍治疗方法。
