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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 the cytological and behavioral effects of serotonin 1A (5-HT_ (1A)) receptor agonist 8-OH-DPAT on levodopa-induced motor complications. Methods Animal models of Parkinson disease (PD) were established by stereotactic injection of 6-hydroxydopamine into the medial forebrain bundle of forebrain in rats. Two sets of experiments were performed in a model-successful PD rat: In the first set of experiments, three groups of PD rats received intraperitoneal injections of 2 times daily levodopa methyl ester (50 mg / kg plus 12.5 mg / kg benserazide) for 22 days . Three groups of PD rats received 8-OH-DPAT, 8-OH-DPAT + 5-HT (1A) (5-HT 1A) blockers WAY-100635 (0.1mg / kg) and solvent control. In the second experiment, two groups of PD rats received levodopa / benserazide + 8-OH-DPAT and levodopa / Hydrazine + Solvent for 22d. The rotation time and the frequency of occurrence of off-cycle were evaluated. The subcellular distribution of glutamate receptor 1 (GluR1) in striatum and the phosphorylation of GluR1 serine (GluR1Ser845) in GluR1 were detected by Western blotting. Results 8-OH-DPAT reversed the shortening of rotation time induced by levodopa in PD rats by about 27.8% ± 6.1%, and reduced the incidence of off-period by about 7.2% ± 1.7%. The combination of 5-HT 1A receptor antagonist WAY-100635 and 8-OH-DPAT abolished the effect of 8-OH-DPAT, suggesting that the observed effect of 8-OH-DPAT is through 5-HT_ (1A) receptor. In addition, 8-OH-DPAT regulates the subcellular distribution of GluR1, which is closely related to motor complications, and decreases the phosphorylation level of GluR1Ser845 by about 22.1% ± 3.5%. Conclusions The drugs that stimulate the 5-HT 1A receptor may be useful in the treatment and prevention of PD motor complications.