Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models
Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models
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DOI：
10.1212/wnl.57.10.1829
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发表时间：
2001-11-27
期刊：
影响因子：
9.9
通讯作者：
Chase, TN
中科院分区：
文献类型：
--
作者：
Bibbiani, F;Oh, JD;Chase, TN
背景：已知基底神经节中的5-羟色胺能传递影响多巴胺能机制和运动功能。目的：评估多巴胺能5-HT 1A自身受体（通过调节外源性左旋多巴形成的5-羟色胺和多巴胺的释放）影响左旋多巴治疗PD时反应改变的可能性。研究方法：将5-HT 1A受体激动剂sarizotan（EMD 128130）单独全身给药，并与左旋多巴一起全身给药帕金森病大鼠和非人灵长类动物。结果如下：在6-羟基多巴胺损伤的大鼠中，sarizotan（2.5 mg/kg PO）对左旋多巴的急性旋转反应没有影响，但确实减弱了慢性左旋多巴治疗引起的运动反应持续时间缩短。在1-甲基-4-苯基-1，2，3，6-四氢吡啶损伤的猴中，sarizotan（2 mg/kg PO）单独给药对帕金森病的严重程度或对左旋多巴的抗帕金森病反应没有影响。相反，相同剂量的sarizotan使左旋多巴诱导的舞蹈样运动障碍减少了91 +/-5.9%。在这两个物种中，选择性5-HT 1A拮抗剂WAY 100635（0.1 mg/kg SC）阻断了sarizotan的运动效应，表明观察到的sarizotan反应可能是在5-HT 1A自身受体介导的。结论：刺激5-HT 1A受体的药物可用于治疗帕金森病患者的运动反应并发症。
Background: Serotoninergic transmission in the basal ganglia is known to influence dopaminergic mechanisms and motor function. Objective: To evaluate the possibility that serotoninergic 5-HT1A autoreceptors (by regulating the release of serotonin as well as dopamine formed from exogenous levodopa) affect the response alterations complicating levodopa treatment of PD. Methods: The 5-HT1A receptor agonist sarizotan (EMD128130) was systemically administered alone and together with levodopa to parkinsonian rats and nonhuman primates. Results: In 6-hydroxydopamine-lesioned rats, sarizotan (2.5 mg/kg PO) had no effect on the acute rotational response to levodopa but did attenuate the shortening in motor response duration induced by chronic levodopa treatment. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, sarizotan (2 mg/kg PO) alone had no effect on parkinsonian severity or on the antiparkinsonian response to levodopa. In contrast, the same dose of sarizotan reduced levodopa-induced choreiform dyskinesias by 91 +/- 5.9%. In both species, the motoric effects of sarizotan were blocked by the selective 5-HT1A antagonist WAY100635 (0.1 mg/kg SC), indicating that the observed sarizotan responses were probably mediated at the 5-HT1A autoreceptor. Conclusion: Pharmaceuticals acting to stimulate 5-HT1A receptors could prove useful in the treatment of the motor response complications in parkinsonian patients.