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目的:探讨5-HT1A受体激动剂8-OH-DPAT对左旋多巴诱发的异动症细胞学与行为学效应。方法:6-羟基多巴胺立体定向注射至大鼠前脑内侧束建立帕金森病(PD)动物模型。对模型成功的PD大鼠进行两套实验:第1套实验中3组PD大鼠接受每日2次左旋多巴(50mg穔g-1加苄丝肼12.5mg穔g-1)腹腔注射,持续22d。在第23天左旋多巴注射前,3组PD大鼠先分别接受8-OH-DPAT、8-OH-DPAT+5-HT1A受体阻断剂WAY-1006350.1mg穔g-1及溶剂;第2套实验中2组PD大鼠每日2次分别接受左旋多巴/苄丝肼+8-OH-DPAT与左旋多巴/苄丝肼+溶剂,持续22d。评估剂峰旋转次数;采用蛋白印迹法检测纹状体区谷氨酸受体亚型GluR1亚细胞分布及GluR1Ser831磷酸化的表达情况。结果:8-OH-DPAT减轻了PD大鼠的剂峰旋转次数。5-HT1A受体阻断剂WAY-100635与8-OH-DPAT联合应用则消除了8-OH-DPAT的效应。此外,8-OH-DPAT能调节与异动症相关的GluR1的亚细胞分布且明显降低GluR1Ser831的磷酸化水平。结论:8-OH-DPAT是通过5-HT1A受体起作用的,激动5-HT1A受体的药物可能对于PD异动症治疗及预防有益。
Objective: To investigate the cytological and behavioral effects of 5-HT1A receptor agonist 8-OH-DPAT on levodopa-induced dyskinesia. Methods: The animal model of Parkinson’s disease (PD) was established by stereotactic injection of 6-hydroxydopamine into medial forebrain of rats. Two sets of experiments were performed on a model-successful PD rat: In the first set of experiments, three groups of PD rats received intraperitoneal injections twice daily of levodopa (50 mg 穔 g-1 plus benserazide 12.5 mg 穔 g-1) Lasts 22d. Before the injection of levodopa on day 23, three groups of PD rats received 8-OH-DPAT and 8-OH-DPAT + 5-HT1A receptor blockers WAY-1006350.1 mg 穔 g-1 and solvent respectively. Two groups of PD rats received levodopa / benserazide + 8-OH-DPAT and levodopa / benserazide + solvent twice daily for 2 days. The number of peak rotation was evaluated. The glutamate receptor subtype GluR1 subcellular distribution and phosphorylation of GluR1Ser831 in striatum were detected by Western blotting. Results: 8-OH-DPAT reduced the number of peak rotation in PD rats. The combination of 5-HT1A receptor blocker WAY-100635 and 8-OH-DPAT abolished the effect of 8-OH-DPAT. In addition, 8-OH-DPAT regulates subcellular distribution of GluR1 associated with dyskinesia and significantly reduces GluR1 Ser831 phosphorylation. Conclusions: 8-OH-DPAT acts through the 5-HT1A receptor and drugs that agonize the 5-HT1A receptor may be beneficial for the treatment and prophylaxis of PD.