MK801对左旋多巴诱导异动症大鼠行为的影响及其机制研究

Effect of MK801 on the behavior of LID rat model and the possible mechanisms

目的探讨MK801对左旋多巴诱导异动症(LID)大鼠模型行为的影响及其可能作用机制。方法观察MK801治疗LID大鼠的行为变化,并用免疫组织化学方法和逆转录聚合酶链反应技术(RTPCR)检测大鼠纹状体区FosB和前脑啡肽原(PPE)及前脑强啡肽原(PDyn)基因的表达情况。用辣根过氧化物酶(HRP)逆行示踪与免疫组织化学相结合的双重反应技术观测FosB的细胞分布状况。结果帕金森病(PD)大鼠慢性间断性应用左旋多巴后出现明显的异常不自主运动,与人类LID具有相似特征。LID大鼠损毁侧纹状体区FosB阳性神经元增多,PPEmRNA和PDynmRNA表达明显增加,MK801治疗使LID大鼠异常不自主运动评分减少,分别为(419±156)和(72±30)分;伴随纹状体区FosB和PDynmRNA表达减少,而PPEmRNA表达无明显改变。FosB主要分布于纹状体黑质神经元内。结论MK801能阻止大鼠LID的发生,其机制可能与阻断了直接通路上即早基因FosB及其下游靶基因强啡肽的产生有关,表明LID的发生与直接通路的活动异常密切相关。

Objective To study the effect of MK801 on behavioral changes and the possible mechanisms. Methods To observe the behavioral changes of levodopa induced dyskinesia (LID) rats during the period of chronic MK801 treatment, immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to measure the changes in expression of FosB, preproenkephalin (PPE) mRNA and prodynorphin (PDyn) mRNA in striatum, respectively. Double labling technique including immunohistochemistry of FosB and retrograde HRP transport tracing was used to observe the cell distribution of FosB. Results Pulsatile treatment with levodopa induced Abnormal involuntary movements (AIM) in PD rats, similar to LID in PD patients. FosB positive neurons and expressions of PPE mRNA and PDyn mRNA in striatum of 6-OHDA-lesioned hemisphere were increased in LID rats, and AIM scores of LID rats were reduced by MK801 treatment(41.9±15.6 vs 7.2±3.0), accompanied by the decrease in expressions of FosB and PDyn mRNA, but not PPE mRNA. Neurons immunoreactive for FosB were mainly located in striatonigral neurons which were labeled by cholera toxin-HRP (CT-HRP) injected in the substantia nigra pars reticulata (SNr). Conclusions MK801 could prevent the occurrence of dyskinesias induced by chronic levodopa treatment. The mechanism might be involved in the high expression of immediate early gene FosB and specific gene PDyn on the direct pathway. It suggests that LID might be related to the abnormal activity of direct pathway.