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首页> 外文期刊>The European Journal of Neuroscience >Serotonin transporter inhibition attenuates l-DOPA-induced dyskinesia without compromising l-DOPA efficacy in hemi-parkinsonian rats
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Serotonin transporter inhibition attenuates l-DOPA-induced dyskinesia without compromising l-DOPA efficacy in hemi-parkinsonian rats

机译：血清素转运蛋白抑制可减轻l-DOPA引起的运动障碍，而不会损害半帕金森病大鼠的l-DOPA功效

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Long-term dopamine replacement therapy with l-DOPA in Parkinson's disease often leads to the development of abnormal involuntary movements known as l-DOPA-induced dyskinesia. Growing evidence suggests that, following dopamine cell loss, serotonin neurons acting as surrogates for dopaminergic processes take up l-DOPA, convert it to dopamine and release it in an unregulated fashion that precipitates dyskinesia. Although most studies have focused on serotonin 5-HT 1 receptor stimulation as an antidyskinetic strategy, targeting the serotonin transporter modulation of dopamine activity has been overlooked. Therefore, in the current study, selective serotonin reuptake inhibitors were tested for their ability to reduce l-DOPA- and apomorphine-induced dyskinesia. In Experiments 1 and 2, hemi-parkinsonian rats were primed with l-DOPA until stable dyskinesia developed. Rats in Experiment 1 were administered the selective serotonin reuptake inhibitors paroxetine, citalopram or fluoxetine, followed by l-DOPA. Abnormal involuntary movements and forepaw adjusting steps were recorded to determine the effects of these compounds on dyskinesia and motor performance, respectively. Brains were collected on the final test day, after which striatal and raphe monoamines were examined via high-performance liquid chromatography. In Experiment 2, dyskinesias were measured after selective serotonin reuptake inhibitors and apomorphine. Serotonin reuptake inhibitors dose-dependently attenuated l-DOPA- but not apomorphine-induced dyskinesia, and preserved l-DOPA efficacy. Neurochemically, serotonin transporter inhibition enhanced striatal and raphe serotonin levels and reduced its turnover, indicating a potential mechanism of action. The present results support targeting serotonin transporters to improve Parkinson's disease treatment and provide further evidence for the role of the serotonin system in l-DOPA's effects.
机译：在帕金森氏病中用l-DOPA长期进行多巴胺替代疗法通常会导致异常的非自愿运动的发展，这种运动被称为l-DOPA引起的运动障碍。越来越多的证据表明，在多巴胺细胞丢失后，充当多巴胺能过程替代物的5-羟色胺神经元吸收了l-DOPA，将其转化为多巴胺并以不受管制的方式释放，从而导致运动障碍。尽管大多数研究都将5-羟色胺5-HT 1受体刺激作为一种抗运动障碍的策略，但是针对5-羟色胺转运蛋白调节多巴胺活性的研究却被忽略了。因此，在当前的研究中，测试了选择性5-羟色胺再摄取抑制剂减轻l-DOPA和阿朴吗啡引起的运动障碍的能力。在实验1和2中，用1-DOPA灌注半帕金森病大鼠，直到出现稳定的运动障碍。实验1的大鼠被给予选择性5-羟色胺再摄取抑制剂帕罗西汀，西酞普兰或氟西汀，然后是1-DOPA。记录异常的非自愿运动和前爪调节步骤，分别测定这些化合物对运动障碍和运动能力的影响。在最后的测试日收集大脑，然后通过高效液相色谱法检查纹状体和萘甲胺。在实验2中，在选择血清素再摄取抑制剂和阿扑吗啡后测量了运动障碍。 5-羟色胺再摄取抑制剂可剂量依赖性地减弱1-DOPA-但不会减弱阿扑吗啡引起的运动障碍，并保留1-DOPA的功效。从神经化学上讲，5-羟色胺转运蛋白的抑制作用增强了纹状体和蛛网膜5-羟色胺的水平，并减少了其转换，表明了其潜在的作用机理。本研究结果支持靶向5-羟色胺转运蛋白以改善帕金森氏病的治疗，并为5-羟色胺系统在1-DOPA效应中的作用提供了进一步的证据。

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