Neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct:: Evidence from the effects of the alpha2 adrenoceptor antagonist idazoxan
Neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct:: Evidence from the effects of the alpha2 adrenoceptor antagonist idazoxan
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DOI：
10.1002/mds.1148
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发表时间：
2001-07-01
影响因子：
8.6
通讯作者：
Brotchie, JM
中科院分区：
文献类型：
--
作者：
Fox, SH;Henry, B;Brotchie, JM
继发于多巴胺替代疗法的运动障碍是目前帕金森病可用疗法的主要并发症。α（2）肾上腺素受体拮抗剂，如咪唑克生，可显著减少1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）损伤的非人灵长类帕金森病模型和人类中左旋多巴诱导的运动障碍。肾上腺素受体拮抗剂的这种作用可能涉及阻断左旋多巴合成的去甲肾上腺素的作用。我们假设，因为多巴胺受体激动剂，如阿扑吗啡，不能代谢产生去甲肾上腺素，肾上腺素受体的激活可能不参与由这些代理商产生的运动障碍。如果是这样的话，咪唑克生将不会减少阿扑吗啡诱导的运动障碍。MPTP损伤的绒猴与长期左旋多巴治疗诱导的稳定的运动障碍给予阿扑吗啡（0.3毫克/公斤皮下注射）或左旋多巴（8.0毫克/公斤口服）的急性挑战，这些剂量产生等效的峰值剂量的运动障碍。伊达克生（2.5 mg/kg口服），或赋形剂，然后与阿扑吗啡或左旋多巴一起给药。咪唑克生消除了左旋多巴诱导的运动障碍，但不影响阿扑吗啡诱导的运动障碍（分别为P < 0.05 and P >0.05，Wilcoxon配对检验）。咪唑克生也延长了左旋多巴的抗帕金森病作用，但不影响阿扑吗啡的作用，因此，帕金森病中左旋多巴诱导的运动障碍和阿扑吗啡诱导的运动障碍的神经机制的药理学特征似乎是不同的，至少就α 2肾上腺素受体的参与而言。具体地说，左旋多巴，而不是阿扑吗啡诱导的运动障碍，涉及肾上腺素受体的激活。这一发现可能对理解运动障碍具有重要意义，在设计左旋多巴或多巴胺受体激动剂激发的临床研究以评估药物的潜在抗运动障碍特性时应牢记在心。(C)2001运动障碍协会。
Dyskinesia, secondary to dopamine replacement therapy, is the major complication of currently available therapies for Parkinson's disease. Alpha(2) adrenoceptor antagonists, such as idazoxan, can significantly reduce levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, nonhuman primate model of Parkinson's disease and in human. This action of adrenoceptor antagonists may involve blockade of the actions of noradrenaline synthesised from levodopa. We hypothesise that, because dopamine receptor agonists, such as apomorphine, cannot be metabolised to produce noradrenaline, activation of adrenoceptors may not be involved in dyskinesia produced by such agents. If this were the case, idazoxan would not be expected to reduce apomorphine-induced dyskinesia.MPTP-lesioned marmosets with stable dyskinesia induced by prolonged levodopa therapy were given an acute challenge with apomorphine (0.3 mg/kg subcutaneously) or levodopa (8.0 mg/kg orally), these doses produced equivalent peak-dose dyskinesia. Idazoxan (2.5 mg/kg p.o.), or vehicle, was then administered with either apomorphine or levodopa. Idazoxan abolished levodopa-induced dyskinesia but did not affect apomorphine-induced dyskinesia (P < 0.05 and P > 0.05, respectively, Wilcoxon matched pairs test). Idazoxan also extended the anti-parkinsonian actions of levodopa but did not affect those of apomorphine.The pharmacological characteristics of the neural mechanisms underlying levodopa-induced dyskinesia and apomorphine-induced dyskinesia in parkinsonism thus appear to be distinct, at least with respect to the involvement of alpha(2) adrenoceptors. Specifically, levodopa, but not apomorphine-induced dyskinesia, involves activation of adrenoceptors. This finding may have major implications for understanding dyskinesia and should be borne in mind when designing clinical studies in which levodopa or dopamine receptor agonist challenges are employed to assess potential anti-dyskinetic properties of drugs. (C) 2001 Movement Disorder Society.