Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, New York, USA.
Mov Disord. 2018 Nov;33(11):1740-1749. doi: 10.1002/mds.100.
The serotonergic system is a well-established modulator of l-dopa-induced dyskinesia. To date, targeting serotonin transporters or serotonin receptor subtype 1A (5-HT ) reduces l-dopa-induced dyskinesia in animal models; however, these strategies have failed to translate clinically. Ideally, a compound acting at both known antidyskinetic sites could optimize serotonin-mediated approaches. Vilazodone is a selective serotonin reuptake inhibitor and a partial 5-HT agonist approved by the U.S. Food and Drug Administration, situating Vilazodone in a unique position to reduce l-dopa-induced dyskinesia without compromising l-dopa-mediated motor improvements.
The goal of the present study was to characterize Vilazodone's effects on l-dopa-induced behaviors, neurochemistry and gene expression in unilateral 6-hydroxydopamine-lesioned hemi-parkinsonian rats.
In experiments 1 and 2, l-dopa-naïve and l-dopa-primed animals were coadministered Vilazodone and l-dopa daily for 3 weeks to model subchronic use, and behavioral, neurochemical, and messenger RNA (mRNA) expression changes were measured. In experiment 3, dyskinetic behavior was assessed following 5-HT or serotonin receptor subtype 1B blockade prior to Vilazodone-l-dopa coadministration.
Vilazodone significantly suppressed developing and established l-dopa-induced dyskinesia without compromising the promotor effects of l-dopa therapy. In the dopamine-depleted striatum, Vilazodone-l-dopa cotreatment increased dopamine content, suggesting a normalization of dopamine kinetics in dyskinetic brain, and reduced l-dopa-induced c-Fos and preprodynorphin mRNA overexpression, indicative of attenuated dopamine D receptor-mediated direct pathway overactivity. Only 5-HT antagonism partially attenuated Vilazodone's antidyskinetic efficacy, suggesting both serotonin transporter-dependent effects and 5-HT receptors in Vilazodone's actions.
Our findings show Vilazodone has a serotonin-dependent effect on rodent l-dopa-induced dyskinesia and implicate the potential for repositioning Vilazodone against l-dopa-induced dyskinesia development and expression in Parkinson's disease patients. © 2018 International Parkinson and Movement Disorder Society.
血清素能系统是一种成熟的左旋多巴诱导运动障碍的调制器。迄今为止，靶向 5-羟色胺转运体或 5-羟色胺受体 1A（5-HT ）可减少动物模型中的左旋多巴诱导运动障碍；然而，这些策略在临床上都没有成功。理想情况下，一种作用于已知抗运动障碍部位的化合物可以优化 5-羟色胺介导的方法。维拉唑酮是一种被美国食品和药物管理局批准的选择性 5-羟色胺再摄取抑制剂和部分 5-HT 激动剂，使维拉唑酮处于独特的位置，可以减少左旋多巴诱导的运动障碍，而不影响左旋多巴介导的运动改善。
本研究的目的是描述维拉唑酮对单侧 6-羟多巴胺损伤的半帕金森病大鼠中左旋多巴诱导的行为、神经化学和基因表达的影响。
在实验 1 和 2 中，左旋多巴-naive 和左旋多巴-primed 动物每天共给予维拉唑酮和左旋多巴 3 周，以模拟亚慢性使用，并测量行为、神经化学和信使 RNA（mRNA）表达的变化。在实验 3 中，在维拉唑酮-左旋多巴共给药前，通过 5-HT 或 5-HT 受体 1B 阻断评估运动障碍行为。
维拉唑酮显著抑制了发展中和已建立的左旋多巴诱导的运动障碍，而不影响左旋多巴治疗的启动作用。在多巴胺耗竭的纹状体中，维拉唑酮-左旋多巴联合治疗增加了多巴胺含量，表明运动障碍大脑中多巴胺动力学的正常化，并减少了左旋多巴诱导的 c-Fos 和前原啡肽 mRNA 的过度表达，表明多巴胺 D 受体介导的直接通路过度活动减弱。只有 5-HT 拮抗作用部分减弱了维拉唑酮的抗运动障碍作用，表明维拉唑酮的作用既依赖于 5-羟色胺转运体，也依赖于 5-HT 受体。
我们的发现表明，维拉唑酮对大鼠左旋多巴诱导的运动障碍有 5-羟色胺依赖性作用，并提示重新定位维拉唑酮对抗帕金森病患者左旋多巴诱导的运动障碍发展和表达的潜力。
