Chronic psychostimulant exposure and vulnerability to Parkinson's disease: is there a role for brain iron?

Alterations in brain iron homeostasis have been reported in Parkinson's disease (PD) and Attention Deficit/Hyperactivity Disorder (ADHD). Recent evidence suggests a potential link between ADHD and an increased risk of PD onset, with psychostimulant exposure--particularly methylphenidate (MPH)--as a possible contributing factor. A growing body of evidence indicates an association between chronic MPH exposure and increased striatal and nigral iron content in children with ADHD. Elevated iron levels in the nigrostriatal pathway are thought to contribute to PD pathophysiology. In this perspective paper, we describe the interplay between dopamine autoxidation, inhibition of mitochondrial complex I, and increased cellular iron accumulation. We then discuss how alterations in membrane transporters following chronic MPH exposure may disrupt dopamine compartmentalization and promote dopamine autoxidation in nigrostriatal dopaminergic terminals. Finally, we review preliminary neuroimaging evidence of increased nigrostriatal iron content in predominantly MPH-medicated children with ADHD compared with medication-naïve children and neurotypical controls, and we propose recommendations to further evaluate this putative relationship. Importantly, evidence is preliminary, and the proposed hypothetical model should not be used to guide clinical practice currently.