Flores Andrew J, Bartlett Mitchell J, So Lisa Y, Laude Nicholas D, Parent Kate L, Heien Michael L, Sherman Scott J, Falk Torsten
Department of Neurology, University of Arizona, Tucson, AZ 85724, USA; Graduate Interdisciplinary Program in Physiological Sciences, University of Arizona, Tucson, AZ 85724, USA.
Department of Neurology, University of Arizona, Tucson, AZ 85724, USA.
Neurosci Lett. 2014 Apr 3;564:48-52. doi: 10.1016/j.neulet.2014.02.004. Epub 2014 Feb 11.
Dopamine-replacement therapy with l-DOPA is still the gold standard treatment for Parkinson's disease (PD). One drawback is the common development of l-DOPA-induced dyskinesia (LID) in patients, which can be as disabling as the disease itself. There is no satisfactory adjunct therapy available. Glutamatergic transmission in the basal ganglia circuitry has been shown to be an important player in the development of LID. The N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 has previously been shown to reduce l-DOPA-induced abnormal involuntary movements (AIMs) in a rat preclinical model but only at concentrations that worsen parkinsonism. We investigated the contribution of the direct and indirect striatofugal pathways to these effects. In the direct pathway, dopamine D1 receptors (D1R) are expressed, whereas in the indirect pathway, dopamine D2 receptors (D2R) are expressed. We used the 6-hydroxydopamine-lesioned hemi-parkinsonian rat model initially primed with l-DOPA to induce dyskinesia. When the rats were then primed and probed with the D1R agonist SKF81297, co-injection of MK-801 worsened the D1R-induced limb, axial, and orolingual (LAO) AIMs by 18% (predominantly dystonic axial AIMs) but did not aggravate parkinsonian hypokinesia as reflected by a surrogate measure of ipsiversive rotations in this model. In contrast, when the rats were then primed and probed with the D2R agonist quinpirole, co-injection of MK-801 reduced D2R-induced LAO AIMs by 89% while inducing ipsiversive rotations. The data show that only inhibition of the indirect striatopallidal pathway is sufficient for the full anti-dyskinetic/pro-parkinsonian effects of the NMDA receptor antagonist MK-801, and that MK-801 modestly worsens dyskinesias that are due to activation of the direct striatonigral pathway alone. This differential activation of the glutamatergic systems in D1R- and D2R-mediated responses is relevant to current therapy for PD which generally includes a mixture of dopamine agonists and l-DOPA.
左旋多巴的多巴胺替代疗法仍然是帕金森病（PD）的金标准治疗方法。一个缺点是患者中常见左旋多巴诱导的运动障碍（LID），其可能与疾病本身一样致残。目前没有令人满意的辅助治疗方法。基底神经节回路中的谷氨酸能传递已被证明是LID发生发展的重要因素。N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801先前已被证明在大鼠临床前模型中可减少左旋多巴诱导的异常不自主运动（AIMs），但仅在会加重帕金森病症状的浓度下有效。我们研究了直接和间接纹状体传出通路对这些效应的作用。在直接通路中，表达多巴胺D1受体（D1R），而在间接通路中，表达多巴胺D2受体（D2R）。我们使用6-羟基多巴胺损伤的半帕金森病大鼠模型，最初用左旋多巴引发运动障碍。当大鼠随后用D1R激动剂SKF81297引发并探测时，共注射MK-801使D1R诱导的肢体、轴向和口面部（LAO）AIMs恶化了18%（主要是张力障碍性轴向AIMs），但并未加重帕金森病性运动迟缓，在该模型中通过同侧旋转的替代指标反映。相反，当大鼠随后用D2R激动剂喹吡罗引发并探测时，共注射MK-801使D2R诱导的LAO AIMs减少了89%，同时诱导同侧旋转。数据表明，只有抑制间接纹状体苍白球通路才足以实现NMDA受体拮抗剂MK-801的完全抗运动障碍/促帕金森病作用，并且MK-801会适度加重仅由直接纹状体黑质通路激活引起的运动障碍。谷氨酸能系统在D1R和D2R介导的反应中的这种差异激活与目前的PD治疗相关，目前的治疗通常包括多巴胺激动剂和左旋多巴的混合物。
