Role of zinc in the pathogenesis of attention-deficit hyperactivity disorder: implications for research and treatment.
The dopamine transporter is regulated by zinc (Zn2+), which directly interacts with the transporter protein as a potent non-competitive blocker of substrate translocation (dopamine transport inward and outward). The fact that dysfunction of the dopamine transporter is involved in the pathogenesis of attention-deficit hyperactivity disorder (ADHD) is interesting in the context of studies that suggest the involvement of zinc deficiency in patients with ADHD. In this article, we present a hypothesis exploring the causative mechanism of zinc deficiency in ADHD and why zinc might be beneficial as a supplementary medication and/or adjunct to psychostimulants (methylphenidate, amfetamine) in zinc-deficient ADHD patients. The hypothesis is based on published in vitro observations that the human dopamine transporter contains a high-affinity zinc binding site (His-193, His-375, Glu-396) on its extracellular face that modulates transporter function, and in vivo studies suggesting that response to stimulants is reduced in zinc-deficient ADHD patients. It seems likely that zinc supplementation in zinc-deficient ADHD patients improves the binding status of insufficiently occupied zinc binding sites on the dopamine transporter. We propose to test our hypothesis by recruiting zinc-deficient ADHD patients who will undergo positron emission tomography with the 11C-raclopride displacement method to investigate whether zinc increases extracellular dopamine levels.
Lepping
Peter
P
Wrexham Academic Department of Mental Health, Betsi Cadwaladr University Health Board and Glyndŵr University, Technology Park, Wrexham, UK. peter.lepping@wales.nhs.uk
Huber
Markus
M
D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000209:etiology*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D019587:Dietary Supplements; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004359:Drug Therapy, Combination; D006801:Humans; D008774:Methylphenidate / Q000627:therapeutic use; D016896:Treatment Outcome; D015032:Zinc / Q000172:deficiency* / Q000627:therapeutic use*
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008774:Methylphenidate; D015032:Zinc
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