5-羟色胺1A受体激动剂8-OH-DPAT改善帕金森病运动并发症的实验研究

5-HT1A receptor agonist 8-OH-DPAT improves motor complications in Parkinson' s disease

目的探讨5-羟色胺1A(5-HT_(1A))受体激动剂8-OH-DPAT 对左旋多巴诱发的运动并发症的细胞学与行为学效应。方法通过6-羟基多巴胺立体定向注射至大鼠前脑内侧前脑束建立帕金森病(Parkinson disease,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次左旋多巴甲酯(50mg/kg 加12.5mg/kg 苄丝肼)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-羟色胺_(1A)(5-HT_(1A))受体阻断剂 WAY-100635(0.1mg/kg)及溶剂对照注射;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。评估旋转时间、关期发生频率情况;采用蛋白印迹法检测纹状体区谷氨酸受体1(GluR1)亚细胞分布及 GluR1的845位丝氨酸(GluR1Ser845)磷酸化的表达情况。结果 8-OH-DPAT 逆转了左旋多巴所诱导的 PD 大鼠旋转时间的缩短,延长约27.8%±6.1%;并使关期发生频率减少约7.2%±1.7%。5-HT_(1A)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,提示所观察到的8-OH-DPAT 的效应是通过5-HT_(1A)受体起作用的。此外,8-OH-DPAT 能调节与运动并发症密切相关的 GluR1的亚细胞分布,且使 GluR1Ser845的磷酸化水平降低约22.1%±3.5%。结论激动5-HT_(1A)受体的药物可能是治疗及预防 PD 运动并发症有益的疗法。

Objective To investigate cellular and behavioural effects of 5-HT1A receptor agonist 8-OH-DPAT in a rat model of levodopa-induced motor complications. Methods The hemi-parkinsonian rat model was produced by stereotaxically injecting 6-OHDA to right medial forebrain bundle（MFB）. Two sets of experiments were performed. First, rats were intraperitoneally treated with levodopa 50 mg/kg plus benserazide 12.5 mg/kg twice a day for 22 days. On day 23, rats intraperitoneally received either 8-OH-DPAT （1 mg/kg） or 8-OH-DPAT plus WAY-100635 （0. 1 mg/kg） or dissolvent with each levodopa dose as controls. In the second set, rats were intraperitoneally treated either with levodopa （50 mg/kg） plus 8-OH-DPAT （1 mg/kg） or levodopa 50 mg/kg plus dissolvent, administered twice daily for 22 consecutive days. Rotational duration and frequency of off period were estimated. After sacrificed, subcellualr distribution of GluR1 and GluR1Ser845 phosphorylation was observed by Western blot. Results 8-OH-DPAT, reversing the shortened rotational duration induced by levodopa, prolonged the rotational duration by 27. 8% ± 6. 1% and reduced the frequency of failures to levodopa by 7.2% ± 1.7%. Co-administration of WAY-100635, a 5-HT1A receptor antagonist, with 8-OH-DPAT eliminated the effect of 8-OH-DPAT on motor complications, indicating that the observed 8-OH-DPAT responses were probably mediated via the 5-HT1A autoreceptor. Moreover, 8-OH-DPAT could regulate subcellular distribution of GluR1 and reduce hyperphosphorylation of GluR1 Ser845 by 22. 1% ± 3.5%, which was closely associated with levodopa-induced motor complications. Conclusions These results suggest that pharmaceuticals stimulating 5-HT1A receptors could be useful in the treatment and prevention of the motor complications in parkinsonian patients.