Ostock Corinne Y, Lindenbach David, Goldenberg Adam A, Kampton Elias, Bishop Christopher
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, USA.
Behav Brain Res. 2014 Aug 15;270:75-85. doi: 10.1016/j.bbr.2014.05.009. Epub 2014 May 13.
Dopamine (DA) replacement with l-DOPA remains the most effective pharmacotherapy for motor symptoms of Parkinson's disease (PD) including tremor, postural instability, akinesia, and bradykinesia. Prolonged L-DOPA use frequently leads to deleterious side effects including involuntary choreic and dystonic movements known as L-DOPA induced dyskinesias (LID). DA loss in PD is frequently accompanied by concomitant noradrenergic (NE) denervation of the locus coeruleus (LC); however, the effects of NE loss on L-DOPA efficacy and LID remain controversial and are often overlooked in traditional animal models of PD. The current investigation examined the role of NE loss in L-DOPA therapy by employing the NE specific neurotoxin anti-DA-beta hydroxylase saporin (αDBH) in a rat model of PD. Rats received unilateral 6-hydroxydopamine lesions of the medial forebrain bundle to deplete nigral DA and intraventricular injection of vehicle (DA lesioned rats) or αDBH (DANE lesioned rats) to destroy NE neurons bilaterally. Results indicated that αDBH infusion drastically reduced NE neuron markers within the LC compared to rats that received vehicle treatment. Behaviorally, this loss did not alter the development or expression of L-DOPA- or DA agonist-induced dyskinesia. However, rats with additional NE lesions were less responsive to L-DOPA's pro-motor effects. Indeed, DANE lesioned animals rotated less and showed less attenuation of parkinsonian stepping deficits following high doses of L-DOPA than DA lesioned animals. These findings suggest that severe NE loss may reduce L-DOPA treatment efficacy and demonstrate that degradation of the NE system is an important consideration when evaluating L-DOPA effects in later stage PD.
用左旋多巴替代多巴胺仍然是治疗帕金森病（PD）运动症状（包括震颤、姿势不稳、运动不能和运动迟缓）最有效的药物疗法。长期使用左旋多巴常常会导致有害的副作用，包括称为左旋多巴诱导的运动障碍（LID）的不自主舞蹈样和肌张力障碍性运动。帕金森病中多巴胺的丧失常常伴随着蓝斑（LC）去甲肾上腺素能（NE）神经支配的同时丧失；然而，去甲肾上腺素丧失对左旋多巴疗效和左旋多巴诱导的运动障碍的影响仍存在争议，并且在传统的帕金森病动物模型中常常被忽视。当前的研究通过在帕金森病大鼠模型中使用去甲肾上腺素特异性神经毒素抗多巴胺-β-羟化酶皂草素（αDBH）来研究去甲肾上腺素丧失在左旋多巴治疗中的作用。大鼠接受内侧前脑束的单侧6-羟基多巴胺损伤以耗尽黑质多巴胺，并脑室内注射溶剂（多巴胺损伤大鼠）或αDBH（去甲肾上腺素-多巴胺损伤大鼠）以双侧破坏去甲肾上腺素能神经元。结果表明，与接受溶剂治疗的大鼠相比，注入αDBH大大降低了蓝斑内的去甲肾上腺素能神经元标志物。在行为上，这种丧失并没有改变左旋多巴或多巴胺激动剂诱导的运动障碍的发生或表现。然而，额外有去甲肾上腺素损伤的大鼠对左旋多巴的促运动作用反应较弱。实际上，与多巴胺损伤的动物相比，去甲肾上腺素-多巴胺损伤的动物在高剂量左旋多巴后旋转较少，帕金森步态缺陷的减轻也较少。这些发现表明，严重的去甲肾上腺素丧失可能会降低左旋多巴的治疗效果，并表明在评估晚期帕金森病中左旋多巴的作用时，去甲肾上腺素系统的退化是一个重要的考虑因素。
