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-1 α-mediated changes in iron homostasis are involved in the Clk1 deficiency-altered METH reward behaviors.

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

[1]Peng-ju Yan;Zhao-xiang Ren;Zhi-feng Shi;Chun-lei Wan;Chao-jun Han;Liu-shuai Zhu;Ning-ning Li;John L.Waddington;Xue-chu Zhen-.Dysregulation of iron homeostasis and methamphetamine reward behaviors in Clk1-deficient mice)[J].中国药理学报（英文版）,2022(07):1686-1698

Clk1,Clk1+,homostasis

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