Quetiapine attenuates levodopa-induced motor complications in rodent and primate parkinsonian models.
Quetiapine attenuates levodopa-induced motor complications in rodent and primate parkinsonian models.
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喹硫平可减轻啮齿动物和灵长类帕金森病模型中左旋多巴引起的运动并发症。
DOI：
10.1006/exnr.2002.8009
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发表时间：
2002
影响因子：
5.3
通讯作者：
Chase,ThomasN
中科院分区：
文献类型：
--
作者：
Oh,JustinD;Bibbiani,Francesco;Chase,ThomasN
帕金森病（PD）运动功能障碍的多巴胺能机制的贡献尚未完全阐明。最近的临床观察越来越多地表明，能够阻断5-羟色胺5 HT 2A/C受体的药物可以使某些锥体外系运动障碍患者受益。为了进一步探索这些和其他神经递质受体在帕金森病体征和左旋多巴诱导的运动障碍发病机制中的作用，我们评估了奎替鲁胺（一种具有5 HT 2A/C和D2/3拮抗活性的非典型抗精神病药）对6-羟基多巴胺损伤大鼠和MPTP损伤非人灵长类动物运动行为的影响。在偏侧帕金森病大鼠中，奎替鲁胺（5 mg/kg，po）可逆转左旋多巴每日两次治疗3周所产生的对左旋多巴激发的缩短的运动反应（P < 0.01）。在接受长期左旋多巴治疗的大鼠中，奎替鲁（5 mg/kg po）还使对多巴胺D1受体激动剂（SKF 38392）或D2受体激动剂（喹吡罗）的急性注射的缩短反应正常化。当单独或与左旋多巴一起给予帕金森病大鼠和猴子时，奎替利对帕金森病功能障碍没有影响。然而，当与左旋多巴联合给药时，奎替鲁胺（4 mg/kg，po）确实显著减少了左旋多巴诱导的运动障碍（P < 0.05）。这些结果表明，奎替鲁肽可以为左旋多巴引起的运动并发症患者提供治疗益处。此外，我们的研究结果可能表明，5 HT 2A/C受体介导的机制，单独或与其他机制相结合，有助于与PD治疗相关的运动反应改变的发病机制。
The contribution of serotoninergic mechanisms to motor dysfunction in Parkinson's disease (PD) has yet to be fully elucidated. Recent clinical observations increasingly suggest that drugs able to block serotonin 5HT2A/C receptors can benefit patients with certain extrapyramidal movement disorders. To further explore the roles of these and other neurotransmitter receptors in the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias; we evaluated the effects of quetiapine, an atypical antipsychotic with 5HT2A/C and D2/3 antagonistic activity, on motor behavior in 6-hydroxydopamine-lesioned rats and MPTP-lesioned nonhuman primates. In hemiparkinsonian rats, quetiapine (5 mg/kg, po) reversed the shortened motor response to levodopa challenge produced by 3 weeks of twice-daily levodopa treatment (P < 0.01). Quetiapine (5 mg/kg po) also normalized the shortened response to the acute injection of either a dopamine D1 receptor agonist (SKF 38392) or a D2 agonist (quinpirole) in rats that had received chronic levodopa treatment. Quetiapine had no effect on parkinsonian dysfunction when given alone or with levodopa to parkinsonian rats and monkeys. Quetiapine (4 mg/kg, po) did, however, substantially reduce levodopa-induced dyskinesias when coadministered with levodopa (P < 0.05). These results suggest that quetiapine could confer therapeutic benefits to patients with levodopa-induced motor complications. Moreover, our findings may indicate that 5HT2A/C receptor-mediated mechanisms, alone or in combination with other mechanisms, contribute to the pathogenesis of the altered motor responses associated with the treatment of PD.