Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA.
Neurobiol Dis. 2013 Feb;50:30-41. doi: 10.1016/j.nbd.2012.09.006. Epub 2012 Sep 23.
L-dopa-induced dyskinesias (LIDs) are abnormal involuntary movements that develop with long term L-dopa therapy for Parkinson's disease. Studies show that nicotine administration reduced LIDs in several parkinsonian animal models. The present work was done to understand the factors that regulate the nicotine-mediated reduction in LIDs in MPTP-lesioned nonhuman primates. To approach this, we used two groups of monkeys, one with mild-moderate and the other with more severe parkinsonism rendered dyskinetic using L-dopa. In mild-moderately parkinsonian monkeys, nicotine pretreatment (300 μg/ml via drinking water) prevented the development of LIDs by ~75%. This improvement was maintained when the nicotine dose was lowered to 50 μg/ml but was lost with nicotine removal. Nicotine re-exposure again decreased LIDs. By contrast, nicotine treatment did not reduce LIDs in monkeys with more severe parkinsonism. We next determined how nicotine's ability to reduce LIDs correlated with lesion-induced changes in the striatal dopamine transporter and (3)H-dopamine release in these two groups of monkeys. The striatal dopamine transporter was reduced to 54% and 28% of control in mild-moderately and more severely parkinsonian monkeys, respectively. However, basal, K(+), α4β2* and α6β2* nAChR-evoked (3)H-dopamine release were near control levels in striatum of mild-moderately parkinsonian monkeys. By contrast, these same release measures were reduced to a significantly greater extent in striatum of more severely parkinsonian monkeys. Thus, nicotine best improves LIDs in lesioned monkeys in which striatal dopamine transmission is still relatively intact. These data suggest that nicotine treatment would most effectively reduce LIDs in patients with mild to moderate Parkinson's disease.
左旋多巴诱导的运动障碍（LIDs）是一种异常的不自主运动，随着长期左旋多巴治疗帕金森病而发展。研究表明，尼古丁给药可减少几种帕金森病动物模型中的 LIDs。本研究旨在了解调节 MPTP 损伤的非人灵长类动物中尼古丁介导的 LIDs 减少的因素。为此，我们使用了两组猴子，一组为轻度至中度帕金森病，另一组为使用左旋多巴引起运动障碍的更严重帕金森病。在轻度至中度帕金森病猴子中，尼古丁预处理（通过饮用水 300μg/ml）可将 LIDs 的发展减少约 75%。当尼古丁剂量降低至 50μg/ml 时，这种改善得以维持，但尼古丁去除后则丧失。尼古丁再次暴露又降低了 LIDs。相比之下，尼古丁治疗不能减少更严重帕金森病猴子的 LIDs。我们接下来确定了尼古丁降低 LIDs 的能力与纹状体多巴胺转运体损伤诱导的变化以及这两组猴子中（3）H-多巴胺释放之间的相关性。纹状体多巴胺转运体在轻度至中度和更严重帕金森病猴子中分别减少至对照的 54%和 28%。然而，轻度至中度帕金森病猴子纹状体中的基础、K+、α4β2和α6β2nAChR 诱发（3）H-多巴胺释放接近对照水平。相比之下，在更严重帕金森病猴子的纹状体中，这些相同的释放测量值减少到了更大的程度。因此，尼古丁在纹状体多巴胺传递仍然相对完整的损伤猴子中最能改善 LIDs。这些数据表明，尼古丁治疗将最有效地减少轻度至中度帕金森病患者的 LIDs。
