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. 2021 Dec 6;43(8):1887–1888. doi: 10.1038/s41401-021-00821-2

Fig. 1. Schematic diagram showing how METH exposure alters cytoplasm iron content, membrane DAT expression, and METH reward.

Fig. 1

Briefly, METH exposure increases Clk1 expression, which subsequently decreases the iron exporter (FPN1) expression, causing an increase in cytoplasm iron content, and also increases lysosomal DAT degradation, causing a reduction in membrane DAT expression. Increased iron content may also facilitate DAT internalization. Accordingly, genetic deletion or pharmacological inhibition of mitochondria Clk1 causes a reduction in cytoplasm iron content and an increase in membrane DAT expression. Increased membrane DAT facilitates DA reuptake from extracellular space and decreases DA response to METH, producing a reduction in METH reward. Similarly, a pharmacological agent that removes excess cytoplasm iron (such as an iron chelator or FPN1 activator) or inhibits DAT internalization would be also effective in attenuation of METH reward and dependence.