Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA.
Neuropharmacology. 2014 Feb;77:1-8. doi: 10.1016/j.neuropharm.2013.09.017. Epub 2013 Sep 22.
Dopamine (DA) replacement therapy with l-DOPA is the standard treatment for Parkinson's disease (PD). Unfortunately chronic treatment often leads to the development of abnormal involuntary movements (AIMs) referred to as L-DOPA-induced dyskinesia (LID). Accumulating evidence has shown that compensatory plasticity in serotonin (5-HT) neurons contributes to LID and recent work has indicated that acute 5-HT transporter (SERT) blockade provides anti-dyskinetic protection. However neither the persistence nor the mechanism(s) of these effects have been investigated. Therefore the current endeavor sought to mimic a prolonged regimen of SERT inhibition in L-DOPA-primed and -naïve hemi-parkinsonian rats. Rats received 3 weeks of daily co-treatment of the selective 5-HT reuptake inhibitors (SSRIs) citalopram (0, 3, or 5 mg/kg) or paroxetine (0, 0.5, or 1.25 mg/kg) with L-DOPA (6 mg/kg) during which AIMs and motor performance were monitored. In order to investigate potential mechanisms of action, tissue levels of striatal monoamines were monitored and the 5-HT(1A) receptor antagonist WAY100635 (0.5 mg/kg) was used. Results revealed that prolonged SSRIs attenuated AIMs expression and development in L-DOPA-primed and -naïve subjects, respectively, without interfering with motor performance. Neurochemical analysis of striatal tissue indicated that a 3 week SERT blockade increased DA levels in L-DOPA-treated rats. Pharmacologically, anti-dyskinetic effects were partially reversed with WAY100635 signifying involvement of the 5-HT1A receptor. Collectively, these findings demonstrate that prolonged SERT inhibition provides enduring anti-dyskinetic effects in part via 5-HT(1A) receptors while maintaining L-DOPA's anti-parkinsonian efficacy by enhancing striatal DA levels.
多巴胺（DA）替代疗法用左旋多巴是治疗帕金森病（PD）的标准治疗方法。不幸的是，慢性治疗往往会导致异常不自主运动（AIMs）的发展，称为左旋多巴诱导的运动障碍（LID）。越来越多的证据表明，5-羟色胺（5-HT）神经元的代偿性可塑性有助于 LID，最近的工作表明，急性 5-羟色胺转运蛋白（SERT）阻断提供抗运动障碍保护。然而，这些效果的持久性和机制都没有被研究过。因此，目前的努力旨在模拟 SERT 在左旋多巴激发和未激发的偏侧帕金森大鼠中的长期抑制作用。大鼠接受 3 周的每日联合治疗，选择性 5-羟色胺再摄取抑制剂（SSRIs）西酞普兰（0、3 或 5mg/kg）或帕罗西汀（0、0.5 或 1.25mg/kg）与左旋多巴（6mg/kg）一起治疗，在此期间监测 AIMs 和运动表现。为了研究潜在的作用机制，监测纹状体中单胺类物质的水平，并使用 5-HT1A 受体拮抗剂 WAY100635（0.5mg/kg）。结果表明，长期 SSRIs 分别减弱了 LID 激发和未激发的 AIMs 表达和发展，而不干扰运动表现。纹状体组织的神经化学分析表明，3 周的 SERT 阻断增加了左旋多巴治疗大鼠的 DA 水平。药理学分析表明，抗运动障碍作用部分被 WAY100635 逆转，表明 5-HT1A 受体的参与。综上所述，这些发现表明，长期 SERT 抑制通过 5-HT1A 受体提供持久的抗运动障碍作用，同时通过增强纹状体 DA 水平来维持左旋多巴的抗帕金森病疗效。
