Clk1 Deficiency Inhibited Methamphetamine-induced Conditioned Place Preference Via Suppressing DAT Degradation

Chronic use of methamphetamine(Meth),one kind of potent synthetic central nervous system(CNS)stimulants,leads to physical and psychological dependence and exerts rewarding effects via competitively inhibiting dopamine transporter(DAT).However,the molecular details of the process are poorly understood.Clkl,as known as Coq7,is a necessary mitochondrial hydroxylase for ubiquinone(UQ)and plays a key role in the electron transport of respiratory chain.In this study,we investigated the role of Clkl in Meth-induced addiction.The Clkl+/-mutant mice demonstrated inhibited Mcth-induced conditioned place preference(CPP)compared with WT mice and Clkl deficiency increased the expression of DAT on cell membrane by suppressing the DAT degradation.To elucidate the signaling mechanism,we found that Clkl deficiency increased the hypoxia inducible factor-1α(HIF-1α)expression and then down-regulated the iron level via increasing iron exporter ferroportin1(FPN1)expression in vivo and in vitro.However,this elevated DAT expression could be reversed by FeSO4 treatment.The results conclusively demonstrated that Clk1 played a key role in the DAT degradation via monitoring iron level to alleviate Meth-induced CPP.