MK-801对左旋多巴诱导异动症大鼠模型基底节区神经元活性的影响

目的:研究NMDA(N-methyl-D-aspartate)受体拮抗剂MK-801对左旋多巴诱导的帕金森病大鼠异常不自主运动行为学及其基底节区Fos表达的影响,探讨谷氨酸对长期左旋多巴治疗后帕金森病大鼠基底节输出通路活性改变的影响。方法:帕金森病大鼠给予左旋多巴治疗28d,第29d左旋多巴治疗前15min腹腔注射MK-801一次。观察其行为学变化,并用免疫组织化学方法观察尾壳核和苍白球Fos表达情况。结果:长期间断左旋多巴治疗后,帕金森病大鼠出现刻板运动和进行性增加的对侧旋转等行为学改变。提前用MK-801抑制了其刻板动作,而增加了对侧旋转行为。与左旋多巴治疗组比较,MK-80l治疗组损毁侧尾壳核区Fos表达明显增多而苍白球区Fos表达明显减少。结论:慢性间断性左旋多巴治疗诱导帕金森病大鼠异常不自主运动和旋转期缩短是帕金森病患者左旋多巴诱导异动症和疗效减退的啮齿类动物模型,谷氨酸在其发生机制中发挥重要作用,NMDA受体拮抗剂可能通过逆转直接通路的活动而抑制异动症和疗效减退的发生。

Effect of MK801 on neuronal activity in the basal ganglia in a rat model of PD with levodopa-induced abnormal involuntary movement

Objective: To study effects of glutamate receptor blockade on behavior and Fos expression in the basal ganglia of Parkinsonian rats with abnormal involuntary movements( AIM) ,and to explore effects of glutamate on changes in activity of striaturn efferent pathway after repetitive levodopatreatment. Methods; Unilateral 6-hvdroxydopamine-lesioned rat model of Parkinson's disease(PD)wastreated with levodopa/benserazide twice daily for 4 weeks. On day 29,the animals were given an acute systemic administration ofMK-801 15min prior to levodopa treatment to observe the behavior changes and 2 hour late,rats were sacrificed and immunohistochemical technique was used to measure changes of Fosexpression in the caudate-putanlen and globus pallidus. Results: Pulsatile treatment with a subthresholddose of levodopa gradually induced AIM,including stereotypydimb dyskinesia,axial dystoma andmastlcatory dyskinesia)towards the side contralateral tO the dopamine-denervated stnatum,and increased contraverslve rotatmn Pretreatment with the non-competmve NMDA antagonist,MK-801, preventedstereotypy but increased contraverslve rotaUon Fos expression ofthe lesioned hemisphere was increased in the caudate-putamen and reduced in the globus pallidus of rats with AIM by MK-801. Conclusions; The neural mechanism underlying levodopa-induced AIM and shorter duration of rotatmn in rat model of PD was very similar to those seen in levodopa-induced dyskinesia(LID)and wearing-off in PD patients and MPTP. treated monkeys, and glutamate may play an important role in pathogenesis Of LID. Glutamate receptor blockade may prevent occurrence of LID and wearing-off through reversing activity of directoutput pathway.