Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, 2, Ireland.
Acta Pharmacol Sin. 2022 Jul;43(7):1686-1698. doi: 10.1038/s41401-021-00806-1. Epub 2021 Nov 22.
Chronic administration of methamphetamine (METH) leads to physical and psychological dependence. It is generally accepted that METH exerts rewarding effects via competitive inhibition of the dopamine transporter (DAT), but the molecular mechanism of METH addiction remains largely unknown. Accumulating evidence shows that mitochondrial function is important in regulation of drug addiction. In this study, we investigated the role of Clk1, an essential mitochondrial hydroxylase for ubiquinone (UQ), in METH reward effects. We showed that Clk1 mutation significantly suppressed METH-induced conditioned place preference (CPP), accompanied by increased expression of DAT in plasma membrane of striatum and hippocampus due to Clk1 deficiency-induced inhibition of DAT degradation without influencing de novo synthesis of DAT. Notably, significantly decreased iron content in striatum and hippocampus was evident in both Clk1 mutant mice and PC12 cells with Clk1 knockdown. The decreased iron content was attributed to increased expression of iron exporter ferroportin 1 (FPN1) that was associated with elevated expression of hypoxia-inducible factor-1α (HIF-1α) in response to Clk1 deficiency both in vivo and in vitro. Furthermore, we showed that iron played a critical role in mediating Clk1 deficiency-induced alteration in DAT expression, presumably via upstream HIF-1α. Taken together, these data demonstrated that HIF-1α-mediated changes in iron homostasis are involved in the Clk1 deficiency-altered METH reward behaviors.
慢性给予甲基苯丙胺（METH）会导致身体和心理依赖。人们普遍认为，METH 通过竞争性抑制多巴胺转运体（DAT）发挥奖赏作用，但 METH 成瘾的分子机制仍知之甚少。越来越多的证据表明，线粒体功能在药物成瘾的调节中很重要。在这项研究中，我们研究了 Clk1（一种对泛醌（UQ）至关重要的线粒体羟化酶）在 METH 奖赏效应中的作用。我们发现 Clk1 突变显著抑制了 METH 诱导的条件性位置偏好（CPP），同时由于 Clk1 缺乏诱导的 DAT 降解抑制，导致纹状体和海马体的质膜 DAT 表达增加，而 DAT 的从头合成不受影响。值得注意的是，Clk1 突变小鼠和 Clk1 敲低的 PC12 细胞中，纹状体和海马体中的铁含量明显减少。铁含量的减少归因于铁输出蛋白 ferroportin 1（FPN1）的表达增加，这与体内和体外 Clk1 缺乏时缺氧诱导因子-1α（HIF-1α）的表达升高有关。此外，我们还表明，铁在介导 Clk1 缺乏引起的 DAT 表达改变中起关键作用，可能是通过上游 HIF-1α。总之，这些数据表明，HIF-1α 介导的铁稳态变化参与了 Clk1 缺乏改变的 METH 奖赏行为。
