Faculté de Pharmacie, Université de Montréal, Montréal, Quebec, Canada.
Groupe de Recherche en Signalisation Moléculaire, Dép. de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, Quebec, Canada.
Mov Disord. 2019 May;34(5):717-726. doi: 10.1002/mds.27630. Epub 2019 Jan 24.
Tardive dyskinesia is a delayed and potentially irreversible motor complication arising from chronic exposure to antipsychotic drugs. Interaction of antipsychotic drugs with G protein-coupled receptors triggers multiple intracellular events. Nevertheless, signaling pathways that might be associated with chronic unwanted effects of antipsychotic drugs remain elusive. In this study, we aimed to better understand kinase signaling associated with the expression of tardive dyskinesia in nonhuman primates.
We exposed capuchin monkeys to prolonged haloperidol (n = 10) or clozapine (n = 6) treatments. Untreated animals were used as controls (n = 6). Half of haloperidol-treated animals (5) developed mild tardive dyskinesia similar to that found in humans. Using Western blots and immunochemistry, we measured putamen total and phosphorylated protein kinase levels associated with canonical and noncanonical signaling cascades of G protein-coupled receptors.
Antipsychotic drugs enhanced pDARPP-32 and pERK1/2, but no difference ws observed in phosphoprotein kinase levels between dyskinetic and nondyskinetic monkeys. On the other hand, comparison of kinase levels between haloperidol-treated dyskinetic and nondyskinetic monkeys indicated that dyskinetic animals had lower GRK6 and β-arrestin2 levels. Levels of pAkt and pGSK-3β were also reduced, but only haloperidol-treated monkeys that developed tardive dyskinesia had reduced pGSK-3β levels, whereas pAkt levels in dyskinetic animals positively correlated with dyskinetic scores. Interestingly, double immunofluorescence labeling showed that putamen dopamine D3 receptor levels were upregulated and that D3/pAkt colocalization was enriched in haloperidol-treated animals displaying tardive dyskinesia.
Our results suggest that upregulation of putamen dopamine D3 receptor and alterations along the noncanonical GRK6/β-arrestin2/Akt/GSK-3β molecular cascade are associated with the development of tardive dyskinesia in nonhuman primates. © 2019 International Parkinson and Movement Disorder Society.
迟发性运动障碍是一种由抗精神病药物慢性暴露引起的延迟且潜在不可逆转的运动并发症。抗精神病药物与 G 蛋白偶联受体的相互作用触发了多种细胞内事件。然而，与抗精神病药物慢性不良反应相关的信号通路仍然难以捉摸。在这项研究中，我们旨在更好地了解与非人类灵长类动物迟发性运动障碍表达相关的激酶信号。
我们使卷尾猴暴露于长期氟哌啶醇（n = 10）或氯氮平（n = 6）治疗中。未治疗的动物用作对照（n = 6）。一半的氟哌啶醇治疗动物（5 只）出现类似于人类的轻度迟发性运动障碍。使用 Western blot 和免疫化学方法，我们测量了与 G 蛋白偶联受体的经典和非经典信号级联相关的纹状体总蛋白激酶和磷酸化蛋白激酶水平。
抗精神病药物增强了 pDARPP-32 和 pERK1/2，但在运动障碍和非运动障碍猴子之间未观察到磷酸化蛋白激酶水平的差异。另一方面，比较氟哌啶醇治疗的运动障碍和非运动障碍猴子之间的激酶水平表明，运动障碍动物的 GRK6 和β-arrestin2 水平较低。pAkt 和 pGSK-3β 的水平也降低，但只有出现迟发性运动障碍的氟哌啶醇治疗猴子的 pGSK-3β 水平降低，而运动障碍动物的 pAkt 水平与运动障碍评分呈正相关。有趣的是，双重免疫荧光标记显示纹状体多巴胺 D3 受体水平上调，并且在出现迟发性运动障碍的氟哌啶醇处理动物中 D3/pAkt 共定位丰富。
我们的结果表明，纹状体多巴胺 D3 受体的上调以及非经典 GRK6/β-arrestin2/Akt/GSK-3β 分子级联中的改变与非人类灵长类动物迟发性运动障碍的发展有关。
