Docosahexaenoic acid reduces haloperidol-induced dyskinesias in mice:: Involvement of Nur77 and retinoid receptors
Docosahexaenoic acid reduces haloperidol-induced dyskinesias in mice:: Involvement of Nur77 and retinoid receptors
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DOI：
10.1016/j.biopsych.2004.06.036
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发表时间：
2004-10-01
影响因子：
10.6
通讯作者：
Lévesque, D
中科院分区：
文献类型：
--
作者：
Éthier, I;Kagechika, H;Lévesque, D
背景：用典型的抗精神病药物治疗精神分裂症的症状显示出一定的疗效，但诱发锥体外系症状是一个严重的障碍，这在很大程度上限制了它们的用途。最近的证据表明，Nur77（神经生长因子诱导的 B）和类维生素A参与与纹状体功能相关的抗精神病药物的生化和行为影响。方法。我们在野生型和 Nur77 缺陷小鼠中评估了维甲酸配体对氟哌啶醇诱导的口腔运动障碍（空虚咀嚼运动）的影响。结果：Nur77 基因消融（敲除）或施用维甲酸拮抗剂可诱导空性咀嚼运动，并加剧氟哌啶醇诱导的空虚咀嚼运动，而维甲酸激动剂二十二碳六烯酸（一种 omega-3 多不饱和脂肪）酸）减少了它们。类维生素A拮抗剂的促运动障碍作用和二十二碳六烯酸的抗运动障碍作用都依赖于Nur77的存在，因为这些药物在Nur77敲除小鼠中仍然没有活性。结论：这些结果表明核受体Nur77和类维生素A X受体参与氟哌啶醇诱导的运动障碍，类维生素A激动剂可能代表了改善典型抗精神病药物治疗的新方法。
Background: Treatment of schizophrenia's symptoms with typical antipsychotic drugs shows some efficacy, but the induction of extrapyramidal symptoms represents a serious handicap, which considerably limits their usefulness. Recent evidence suggests that Nur77 (nerve growth factor-induced B) and retinoids are involved in biochemical and behavioral effects of antipsychotic drugs associated with striatal functions.Methods. We evaluated the effect of retinoid ligands on oral dyskinesias (vacuous chewing movements) induced by haloperidol in wild-type and Nur77-deficient mice.Results: Nur77 gene ablation (knockout) or administration of a retinoid antagonist induced vacuous chewing movements and exacerbated those induced by haloperidol, whereas the retinoid agonist docosahexaenoic acid (an omega-3 polyunsaturated fatty acid) reduced them. Both the prodyskinetic effect of the retinoid antagonist and the antidyskinetic effect of docosahexaenoic acid are dependent on the presence of Nur77, since these drugs remained inactive in Nur77 knockout mice.Conclusion: These results suggest that nuclear receptors Nur77 and retinoid X receptor are involved in haloperidol-induced dyskinesias and that retinoid agonists may represent a new way to improve typical antipsychotic drug therapy.