Blanchet P J, Papa S M, Metman L V, Mouradian M M, Chase T N
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892-1406, USA.
Neurosci Biobehav Rev. 1997 Jul;21(4):447-53. doi: 10.1016/s0149-7634(96)00038-3.
The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl-D-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D1- and D2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonian patients without substantially altering the motor benefit derived from levodopa. These results appear to be in accordance with our 2-deoxyglucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA receptor blockade can attenuate many of the changes in synaptic activity induced by levodopa, particularly in the striatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulation of NMDA receptor-mediated mechanisms contribute to levodopa-induced motor response complications. Additional preclinical and clinical experiments need to be completed with well tolerated glutamate antagonists to determine the full potential of glutamate receptor blockade as a long-term strategy against levodopa-related motor response complications in Parkinson's disease.
基底神经节内复杂的多巴胺 - 谷氨酸相互作用会因慢性黑质纹状体去神经支配和左旋多巴标准替代疗法而受到破坏。急性N - 甲基 - D - 天冬氨酸（NMDA）受体阻断能够克服6 - 羟基多巴胺损伤大鼠长期暴露于左旋多巴所诱导的多巴胺D1和D2依赖性反应变化以及反应持续时间的逐渐缩短。初步结果进一步表明，NMDA受体阻断可抵消1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶损伤的非人灵长类动物和帕金森病患者中左旋多巴诱导的运动障碍，而不会实质性改变左旋多巴带来的运动益处。这些结果似乎与我们在6 - 羟基多巴胺损伤大鼠中的2 - 脱氧葡萄糖研究一致，该研究表明NMDA受体阻断可减轻左旋多巴诱导的许多突触活动变化，特别是在纹状体苍白球复合体中。综上所述，我们的观察结果表明，异常的谷氨酸传递或NMDA受体介导机制的失调导致了左旋多巴诱导的运动反应并发症。需要用耐受性良好的谷氨酸拮抗剂完成更多临床前和临床实验，以确定谷氨酸受体阻断作为对抗帕金森病中左旋多巴相关运动反应并发症的长期策略的全部潜力。
