Serotonin transporter inhibition attenuates l-DOPA-induced dyskinesia without compromising l-DOPA efficacy in hemi-parkinsonian rats.
Serotonin transporter inhibition attenuates l-DOPA-induced dyskinesia without compromising l-DOPA efficacy in hemi-parkinsonian rats.
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DOI：
10.1111/j.1460-9568.2012.08202.x
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Eskow Jaunarajs KL
中科院分区：
文献类型：
--
作者：
Bishop C;George JA;Buchta W;Goldenberg AA;Mohamed M;Dickinson SO;Eissa S;Eskow Jaunarajs KL
在帕金森氏病患者中，长期服用L多巴的多巴胺替代疗法往往会导致异常的不自主运动，称为L多巴诱发的运动障碍。越来越多的证据表明，在多巴胺细胞丢失后，5-羟色胺神经元作为多巴胺能过程的替代品，摄取L-多巴，将其转化为多巴胺，并以一种不受调控的方式释放它，从而导致运动障碍。虽然大多数研究都集中在刺激5-羟色胺5-HT1受体作为抗运动障碍的策略，但靶向5-羟色胺转运体对多巴胺活性的调节却被忽视了。因此，在目前的研究中，选择性5-羟色胺再摄取抑制剂被测试其减少L-多巴和阿朴吗啡诱导的运动障碍的能力。在实验1和实验2中，偏侧帕金森病大鼠被注射L多巴直到出现稳定的运动障碍。实验一大鼠给予选择性5-羟色胺再摄取抑制剂帕罗西汀、西酞普兰或氟西汀，然后给予L多巴。记录异常的不自主运动和前爪调整步骤，以确定这些化合物对运动障碍和运动表现的影响。在最后一次测试当天收集大脑，然后用高效液相色谱法检测纹状体和中缝单胺类物质。在实验2中，观察了选择性5-羟色胺再摄取抑制剂和阿朴吗啡对运动障碍的影响。5-羟色胺再摄取抑制剂呈剂量依赖性地减弱L-多巴的运动障碍，但不能减轻阿朴吗啡诱导的运动障碍，同时保留L-多巴的疗效。神经化学上，5-羟色胺转运体抑制可提高纹状体和中缝的5-羟色胺水平，减少其周转，这表明了一种潜在的作用机制。本研究结果支持以5-羟色胺转运体为靶点来改善帕金森病的治疗，并为5-羟色胺系统在L-多巴的作用中的作用提供了进一步的证据。
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. While most studies have focused on serotonin 5-HT1 receptor stimulation as an anti-dyskinetic strategy, targeting 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, while preserving 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.
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影响因子：
3
作者：
Feyder M;Bonito-Oliva A;Fisone G
通讯作者：
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2.5
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