Methamphetamine (METH) is a potent psychostimulant and one of the most commonly used substances worldwide. METH produces strong rewarding and psychostimulant effects by increasing dopamine (DA) release in the brain reward system. Specifically, METH is first taken into the cytoplasm via the membrane DA transporter (DAT) and then binds to the vesicular monoamine transporter (called “VMAT2”), which blocks DA loading into vesicles and causes cytoplasm DA accumulation. This rapid increase in cytoplasm DA reverses the functional direction of the DAT and releases DA into the extracellular space [1]. As such, DAT has been regarded as a major target in medication development for the treatment of psychostimulant use disorder [2]. Developing new pharmacotherapies for METH addiction is urgent as there are currently none approved by the United States Food and Drug Administration or other authorities. The research highlighted herein presents an exciting new target for METH addiction medication development, Clk1 (clock-1, also called Coq7), a mitochondrial hydroxylase involved in energy metabolism and DAT internalization [3].

It was further demonstrated that Clk1 mutation-induced reduction in METH reward is accompanied by a decrease in cytoplasm iron content [3]. A series of mechanistic experiments revealed that a Clk1 deficit upregulated expression of an iron exporter called ferroportin (FPN1) and decreased expression of hepcidin, a negative FPN1 regulator. As such, the decrease in iron content via Clk1 mutation is likely mediated by augmented iron export activity. These data parallel recent reports showing enhanced iron deposition in the basal ganglia, a critical brain region involved in drug reward and addiction [2], following psychostimulant use [4, 5]. Yan et al. [3] provide the first clear evidence linking mitochondrial Clk1 to altered iron metabolism and intracellular iron levels, which strongly suggests that a Clk1-dependent mechanism could also be involved in METH-induced iron deposition in the basal ganglia. Accordingly, an iron chelator or other pharmacological agents that can remove excess iron accumulation in METH users could also be an effective treatment of METH dependence and addiction (Fig. 1). Prior work has demonstrated that application of the iron chelator deferoxamine can attenuate METH-induced hyperthermia and hyperactivity in rats [6], supporting this line of inquiry. However, further research is required to test the value of iron-depleting agents as pharmacotherapeutics for METH addiction.

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