Der Dopamintransporter (DAT) sorgt für den Rücktransport von Dopamin aus dem synaptischen
Spalt in das präsynaptische Neuron und hat somit eine Schlüsselrolle für die neuronale
Dopaminaktivität. Auffälligkeiten am DAT1-Gen sind bei ADHS beschrieben. Bei unbehandelten
Patienten mit ADHS wurden meist erhöhte DAT-Verfügbarkeiten im SPECT festgestellt,
die durch Methylphenidat (MPH) korrigiert werden können; finden sich primär keine
erhöhten Werte für die DAT-Verfügbarkeit, wirkt MPH kaum oder gar nicht. Wichtige
Beziehungen bestehen zwischen DAT und Zinkstoffwechsel, Nikotinabusus, Alkoholkonsum
sowie Halluzinationen bei psychotischen Patienten. Neuroleptika beeinflussen den Dopaminstoffwechsel
durch die Blockade der postsynaptischen Rezeptoren im Vergleich zu Stimulanzien antagonistisch;
dies wäre eine Erklärung für die klinisch häufig zu beobachtende vermehrte Akathisie
bei Patienten mit ADHS im Rahmen von Narkosen mit Neuroleptika.
The dopamine transporter (DAT) mediates the reuptake of dopamine from the synaptic
cleft into the presynaptic neuron and has a key role for the neuronal dopamine activity.
Involvement of a polymorphism of the DAT1 gene in ADHD has been described. In untreated
patients with ADHD high DAT availability in SPECT has been found in most cases, which
can be corrected by methylphenidate (MPH); patients with low DAT availability seem
not to respond to MPH. Important relations exist between DAT and zinc, nicotine, alcohol
as well as halluzinations in psychotic patients. Neuroleptics influence dopamine metabolism
by blocking the postsynaptic receptors in an antagonistic matter compared to stimulants
; this could be an explanation for the frequently observed akathisia in patients with
ADHD after anesthesia with neuroleptics.
Key Words
dopamine transporter (DAT) - attention deficit/hyperactivity disorder (ADHD) - zinc
- nicotine - DAT1 gene - SPECT
Literatur
- 1
Akhondzadeh S. et al. .
Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit
hyperactivity disorder in children: a double blind and randomized trial.
BMC Psychiatry.
2004;
4
9
- 2
Al Younis ICH.
Attention deficit hyperactivity disorder: neuroimaging before and after treatment
with methylphenidate in children (Abstr).
J Nucl Med.
;
2002;
43
347
- 3
Bilici M. et al. .
Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention
deficit hyperactivity disorder.
Prog Neuropsychopharmacol Biol Psychiatry.
2004;
28
181-190
- 4
Chen N. et al. .
Structure and function of the dopamine transporter.
Eur J Pharmacol.
2000;
405
329-339
- 5
Cheon KA. et al. .
The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter
density in Korean children with attention deficit hyperactivity disorder: relating
to treatment response to methylphenidate.
Eur Neuropsychopharmacol.
2005;
15
95-101
- 6
Cheon KA. et al. .
Dopamine transporter density in the basal ganglia assessed with [123I]IPT SPET in
children with attention deficit hyperactivity disorder.
Eur J Nucl Med Mol Imaging.
2003;
30
306-311
- 7
Dougherty DD. et al. .
Dopamine transporter density in patients with attention deficit hyperactivity disorder.
Lancet.
1999;
354
2132-2133
- 8
Dresel S. et al. .
Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine
transporter before and after methylphenidate treatment.
Eur J Nucl Med.
2000;
27
1518-1524
- 9
Eisenhofer G.
The role of neuronal and extraneuronal plasma membrane transporters in the inactivation
of peripheral catecholamines.
Pharmacol Ther.
2001;
91
35-62
- 10
Fritz GA. et al. .
Propofol dependency in a lay person.
Anesthesiology.
2002;
96
505-506
- 11
Gerlach M. et al. .
Ist ein Parkinson-Syndrom als Spätfolge einer Methylphenidatbehandlung im Kindesalter
möglich?.
Nervenheilkunde.
2003;
22
80-84
- 12
Giros B. et al. .
Cloning and functional characterization of a cocaine-sensitive dopamine transporter.
FEBS Lett.
1991;
295
149-154
- 13
Giros B. et al. .
Cloning, pharmacological characterization, and chromosome assignment of the human
dopamine transporter.
Mol Pharmacol.
1992;
42
383-390
- 14
Gorell JM. et al. .
Smoking and Parkinson's disease: a dose-response relationship.
Neurology.
1999;
52
115-119
- 15 Greenbaum L. et al. .Why do young women smoke? I. Direct and interactive effects
of environment, psychological characteristics and nicotinic cholinergic receptor genes. Mol
Psychiatry, Epub ahead of print 2005
- 16
Hellenbrand W. et al. .
Smoking and Parkinson's disease: a case-control study in Germany.
Int J Epidemiol.
1997;
26
328-339
- 17
Hersch SM. et al. .
Subcellular localization and molecular topology of the dopamine transporter in the
striatum and substantia nigra.
J Comp Neurol.
1997;
388
211-227
- 18
Kirley A. et al. .
Dopaminergic system genes in ADHD: toward a biological hypothesis.
Neuropsychopharmacology.
2002;
27
607-619
- 19
Kollins SH. et al. .
Association between smoking and attention-deficit/hyperactivity disorder symptoms
in a population-based sample of young adults.
Arch Gen Psychiatry.
2005;
62
1142-1147
- 20
Krause J. et al. .
Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Alkoholikern. Ergebnisse einer
Pilotstudie.
Nervenheilkunde.
2002;
21
156-159
- 21 Krause J. et al. .Striatal dopamine transporter availability and DAT-1 gene in
adults with ADHD: no higher DAT availability in patients with homozygosity for the
10-repeat allele. World J Biol Psychiatry: in press
- 22
Krause J. et al. .
Influence of striatal dopamine transporter availability on the response to methylphenidate
in adult patients with ADHD.
Eur Arch Psychiatry Clin Neurosci.
2005;
255
428-431
- 23
Krause J. et al. .
Medikamentöse Therapie der ADHS im Erwachsenenalter.
Psychoneuro.
2005;
31
569-575
- 24
Krause KH. et al. .
Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity
disorder: effects of methylphenidate as measured by single photon emission computed
tomography.
Neurosci Lett.
2000;
285
107-110
- 25
Krause KH. et al. .
Stimulant-like action of nicotine on striatal dopamine transporter in the brain of
adults with attention deficit hyperactivity disorder.
Int J Neuropsychopharmacol.
2002;
5
111-113
- 26
Krause KH. et al. .
The dopamine transporter and neuroimaging in attention deficit hyperactivity disorder.
Neurosci Biobehav Rev.
2003;
27
605-613
- 27 Krause KH. et al. .Is akathisia a frequent side effect of neuroleptics in patients
with attention deficit/hyperactivity disorder (ADHD)?. Anesth Analg: in press
- 28
Loland CJ. et al. .
Defining proximity relationships in the tertiary structure of the dopamine transporter.
Identification of a conserved glutamic acid as a third coordinate in the endogenous
Zn(2+)-binding site.
J Biol Chem.
1999;
274
36928-36934
- 29
Loo SK. et al. .
Functional effects of the DAT1 polymorphism on EEG measures in ADHD.
J Am Acad Child Adolesc Psychiatry.
2003;
42
986-993
- 30
Lott DC. et al. .
Dopamine transporter gene associated with diminished subjective response to amphetamine.
Neuropsychopharmacology.
2005;
30
602-609
- 31
Maiya R. et al. .
Ethanol-sensitive sites on the human dopamine transporter.
J Biol Chem.
2002;
277
30724-30729
- 32
Middleton LS. et al. .
Nicotinic receptor modulation of dopamine transporter function in rat striatum and
medial prefrontal cortex.
J Pharmacol Exp Ther.
2004;
308
367-377
- 33
Moll GH. et al. .
Early methylphenidate administration to young rats causes a persistent reduction in
the density of striatal dopamine transporters.
J Child Adolesc Psychopharmacol.
2001;
11
15-24
- 34
Norregaard L. et al. .
Delineation of an endogenous zinc-binding site in the human dopamine transporter.
EMBO J.
1998;
17
4266-4273
- 35
Oh KS. et al. .
Dopamine transporter genotype influences the attention deficit in Korean boys with
ADHD.
Yonsei Med J.
2003;
44
787-792
- 36
Pifl C. et al. .
Zn2+ modulates currents generated by the dopamine transporter: parallel effects on amphetamine-induced
charge transfer and release.
Neuropharmacology.
2004;
46
223-231
- 37
Ravna AW. et al. .
Molecular model of the neural dopamine transporter.
J Comput Aided Mol Des.
2003;
17
367-382
- 38
Ravna AW. et al. .
Molecular mechanism of citalopram and cocaine interactions with neurotransmitter transporters.
J Pharmacol Exp Ther.
2003;
307
34-41
- 39
Reizer J. et al. .
A functional superfamily of sodium/solute symporters.
Biochim Biophys Acta.
1994;
1197
133-166
- 40
Roman T. et al. .
Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity
disorder.
Pharmacogenetics.
2002;
12
497-499
- 41 Schmitt GJ. et al. .Striatal dopamine transporter availability is associated with
the productive psychotic state in first episode, drug-naive schizophrenic patients. Eur
Arch Psychiatry Clin Neurosci; Epub ahead of print 2005
- 42
Scholze. et al. .
The role of zinc ions in reverse transport mediated by monoamine transporters.
J Biol Chem.
2002;
277
21505-21513
- 43
Shahi GS. et al. .
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: partial protection
against striato-nigral dopamine depletion in C57BL/6J mice by cigarette smoke exposure
and by beta-naphthoflavone-pretreatment.
Neurosci Lett.
1991;
127
247-250
- 44
Torres GE. et al. .
Plasma membrane monoamine transporters: structure, regulation and function.
Nat Rev Neurosci.
2003;
4
13-25
- 45
van Dyck CH. et al. .
Unaltered dopamine transporter availability in adult attention deficit hyperactivity
disorder.
Am J Psychiatry.
2002;
159
309-312
- 46
Vles JS. et al. .
Methylphenidate down-regulates the dopamine receptor and transporter system in children
with attention deficit hyperkinetic disorder (ADHD).
Neuropediatrics.
2003;
34
77-80
- 47
Winsberg BG. et al. .
Association of the dopamine transporter gene (DAT1) with poor methylphenidate response.
J Am Acad Child Adolesc Psychiatry.
1999;
38
1474-1477
Korrespondenzadresse:
Prof. Dr. med. Klaus-Henning Krause
Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München
Ziemssenstr. 1a
80336 München
Email: khkrause@yahoo.com