Dysregulation of iron homeostasis and methamphetamine reward behaviors in Clk1-deficient mice

Acta Pharmacol Sin. 2022 Jul;43(7):1686-1698. doi: 10.1038/s41401-021-00806-1. Epub 2021 Nov 22.

Abstract

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.

Keywords: Clk1; conditioned place preference; dopamine transporter; drug addiction; ferroportin 1; hippocampus; hypoxia-inducible factor-1α; iron; methamphetamine; striatum.

MeSH terms

  • Animals
  • Corpus Striatum / metabolism
  • Homeostasis
  • Iron / metabolism
  • Methamphetamine* / pharmacology
  • Mice
  • Rats
  • Reward

Substances

  • Methamphetamine
  • Iron