title: Role of zinc in the pathogenesis of attention-deficit hyperactivity disorder: implications for research and treatment.
abstract: 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.
authors.affiliation: Wrexham Academic Department of Mental Health, Betsi Cadwaladr University Health Board and Glyndŵr University, Technology Park, Wrexham, UK. peter.lepping@wales.nhs.uk
authors.forename: Peter
authors.initials: P
authors.lastname: Lepping
authors.forename: Markus
authors.initials: M
authors.lastname: Huber
mesh_terms: 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*
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008774:Methylphenidate; D015032:Zinc
references.citation: Neuron. 2000 Apr;26(1):187-96
references.pmid: 10798403
references.citation: Neuropharmacology. 2009 Dec;57(7-8):636-9
references.pmid: 19715711
references.citation: J Clin Psychiatry. 2004;65 Suppl 3:22-6
references.pmid: 15046532
references.citation: Biol Trace Elem Res. 1999 Sep;69(3):261-8
references.pmid: 10468163
references.citation: Nutr Rev. 2008 Oct;66(10):558-68
references.pmid: 18826452
references.citation: Explore (NY). 2009 May-Jun;5(3):171-4
references.pmid: 19409364
references.citation: Hum Genet. 2009 Jul;126(1):51-90
references.pmid: 19506906
references.citation: Biol Psychiatry. 1996 Dec 15;40(12):1308-10
references.pmid: 8959299
references.citation: Synapse. 1993 Apr;13(4):350-6
references.pmid: 8480281
references.citation: Br J Psychiatry. 2010 Mar;196(3):235-40
references.pmid: 20194547
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2004 Jan;28(1):181-90
references.pmid: 14687872
references.citation: Ann Acad Med Stetin. 1998;44:297-314
references.pmid: 9857546
references.citation: J Child Adolesc Psychopharmacol. 2000 Summer;10(2):111-7
references.pmid: 10933121
references.citation: Biol Psychiatry. 2005 Jun 1;57(11):1397-409
references.pmid: 15950014
references.citation: Curr Med Res Opin. 2005 Feb;21(2):195-206
references.pmid: 15801990
references.citation: Nutr Health. 2007;19(1-2):57-60
references.pmid: 18309764
references.citation: J Child Adolesc Psychopharmacol. 2005 Aug;15(4):628-36
references.pmid: 16190794
references.citation: Mol Pharmacol. 1993 Jan;43(1):100-8
references.pmid: 8423763
references.citation: Eur Child Adolesc Psychiatry. 2010 Mar;19(3):237-57
references.pmid: 20145962
references.citation: Reprod Nutr Dev. 2005 Sep-Oct;45(5):549-58
references.pmid: 16188207
references.citation: J Pineal Res. 2009 Aug;47(1):1-7
references.pmid: 19486273
references.citation: Ann Pharmacother. 2010 Jan;44(1):185-91
references.pmid: 20028959
references.citation: Eur J Pharmacol. 2003 Oct 31;479(1-3):199-212
references.pmid: 14612150
references.citation: Eur J Pharmacol. 1994 Jan 1;266(1):87-97
references.pmid: 8137886
references.citation: Arch Gen Psychiatry. 2007 Aug;64(8):932-40
references.pmid: 17679638
references.citation: Eur J Pharmacol. 2003 Oct 31;479(1-3):187-97
references.pmid: 14612149
references.citation: Int Rev Neurobiol. 2009;88:25-41
references.pmid: 19897073
references.citation: Eur J Pharmacol. 2003 Oct 31;479(1-3):153-8
references.pmid: 14612146
references.citation: Nucl Med Biol. 2001 Jul;28(5):561-72
references.pmid: 11516700
references.citation: J Biol Chem. 2004 Nov 26;279(48):49671-9
references.pmid: 15358780
references.citation: Synapse. 2002 Mar 1;43(3):181-7
references.pmid: 11793423
references.citation: J Biol Chem. 2002 Jun 14;277(24):21505-13
references.pmid: 11940571
references.citation: Am J Psychiatry. 1998 Oct;155(10):1325-31
references.pmid: 9766762
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1536-46
references.pmid: 18729135
references.citation: Fortschr Neurol Psychiatr. 2007 May;75(5):275-84
references.pmid: 17443438
references.citation: J Child Adolesc Psychopharmacol. 2005 Aug;15(4):619-27
references.pmid: 16190793
references.citation: J Atten Disord. 2002 Mar;5(4):189-202
references.pmid: 11967475
references.citation: Cost Eff Resour Alloc. 2005 Jun 09;3:5
references.pmid: 15946385
references.citation: Ann N Y Acad Sci. 2010 Feb;1187:316-40
references.pmid: 20201860
references.citation: J Atten Disord. 2002;6 Suppl 1:S31-43
references.pmid: 12685517
references.citation: Lancet. 2005 Jul 16-22;366(9481):237-48
references.pmid: 16023516
references.citation: EMBO J. 1998 Aug 3;17(15):4266-73
references.pmid: 9687495
references.citation: Expert Rev Neurother. 2008 Apr;8(4):611-25
references.pmid: 18416663
references.citation: Br J Psychiatry. 2009 Mar;194(3):204-11
references.pmid: 19252145
references.citation: Biol Psychiatry. 2005 Jun 1;57(11):1410-5
references.pmid: 15950015
references.citation: Am J Clin Nutr. 1996 Dec;64(6):908-15
references.pmid: 8942416
references.citation: BMC Psychiatry. 2004 Apr 08;4:9
references.pmid: 15070418
references.citation: Psychiatr Pol. 1994 May-Jun;28(3):345-53
references.pmid: 8078966
references.citation: Arch Dis Child. 1979 Dec;54(12):909-17
references.pmid: 119488
references.citation: Int J Neurosci. 1990 Jun;52(3-4):239-41
references.pmid: 2269611
references.citation: J Neurochem. 2006 Apr;97 Suppl 1:3-10
references.pmid: 16635244