The NAD(P)H:quinone oxidoreductase 1 (NQO1) gene encodes a cytosolic flavoenzyme that catalyzes the two-electron reduction of quinones to hydroquinones. A polymorphic form of NQO1 is associated with mood disorders such as schizophrenia. However, the role of NQO1 in dopaminergic system has not yet been elucidated. To determine the role of NQO1 in the dopaminergic system, we investigated pharmaco-behavioral effects of d-amphetamine using NQO1-deficienct mice. According to our comparative study involving NQO1+/+ and NQO1-/- mice, NQO1 deficiency increased d-amphetamine-induced psychomotor activity and psychological dependency compared to wild-type mice. Basal and d-amphetamine-induced dopamine levels were also enhanced by NQO1 deficiency. In NQO1-/- mice, neural activation induced by d-amphetamine was higher in dorsolateral striatum, but not in dorsomedial and ventral striata. Although protein level of CaMKIIα, which is a key player in amphetamine-induced dopamine efflux, was decreased in striata of NQO1-/- mice, phosphorylation of CaMKIIα was markedly enhanced in NQO1-/- mice compared to wild-type mice. Interestingly, experiments with pharmacological antagonist showed that D2 antagonist-induced suppression of locomotion required activation of NQO1. Moreover, the rewarding effect in response to D1 agonist was increased by NQO1 deficiency. These results suggest that striatal NQO1 is of considerable interest to understand the mechanism of dopaminergic regulation of psychiatric disorders.

中文翻译：

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NQO1调节d-苯异丙胺在小鼠纹状体多巴胺能系统中的药理行为。

NAD（P）H：醌氧化还原酶1（NQO1）基因编码胞质黄素酶，该酶催化将醌的两个电子还原为对苯二酚。NQO1的多态形式与精神分裂症等情绪障碍有关。然而，NQO1在多巴胺能系统中的作用尚未阐明。为了确定NQO1在多巴胺能系统中的作用，我们使用NQO1缺陷小鼠调查了d-苯异丙胺的药理行为效应。根据我们对NQO1 + / +和NQO1-/-小鼠的比较研究，与野生型小鼠相比，NQO1缺乏症增加了d-苯丙胺诱导的精神运动活动和心理依赖性。NQO1缺乏也会增加基础和d-苯异丙胺诱导的多巴胺水平。在NQO1-/-小鼠中，d-苯异丙胺诱导的神经激活在背外侧纹状体中较高，但不在背卵和腹侧纹状体中。尽管在NQO1-/-小鼠的纹状体中CaMKIIα的蛋白质水平降低，这是苯丙胺诱导的多巴胺流出的关键因素，但与野生型小鼠相比，NQO1-/-小鼠的CaMKIIα磷酸化明显增强。有趣的是，用药理拮抗剂进行的实验表明，D2拮抗剂诱导的运动抑制需要激活NQO1。而且，NQO1缺乏增加了对D1激动剂的响应的奖励作用。这些结果表明，纹状体NQO1对于了解精神疾病的多巴胺能调节机制具有重大意义。与野生型小鼠相比，NQO1-/-小鼠的CaMKIIα磷酸化明显增强。有趣的是，用药理拮抗剂进行的实验表明，D2拮抗剂诱导的运动抑制需要激活NQO1。而且，NQO1缺乏增加了对D1激动剂的响应的奖励作用。这些结果表明，纹状体NQO1对于了解精神疾病的多巴胺能调节机制具有重大意义。与野生型小鼠相比，NQO1-/-小鼠的CaMKIIα磷酸化明显增强。有趣的是，用药理拮抗剂进行的实验表明，D2拮抗剂诱导的运动抑制需要激活NQO1。而且，NQO1缺乏增加了对D1激动剂的响应的奖励作用。这些结果表明，纹状体NQO1对于了解精神疾病的多巴胺能调节机制具有重大意义。