Elsevier

Biological Psychiatry

Volume 57, Issue 3, 1 February 2005, Pages 229-238
Biological Psychiatry

Original articles
Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: Association between striatal dopamine markers and motor hyperactivity

https://doi.org/10.1016/j.biopsych.2004.11.009Get rights and content

Background

The hypothesis that altered dopamine transmission underlies hyperactive-inattentive behavior in children with attention-deficit/hyperactivity disorder (ADHD) is based on genetic studies and the efficacy of psychostimulants. Most of previous positron emission tomography (PET) and single photon emission tomography (SPET) studies have shown altered binding of dopamine markers in the basal ganglia. Yet, the functional role of the neurochemical disturbances are poorly understood. The purpose of our study was to examine dopamine transporter (DAT) and dopamine D2 receptor (D2R) binding in adolescents with ADHD and to search for its relationship with cognitive functions as well as locomotor hyperactivity.

Methods

Twelve adolescents with ADHD and 10 young adults were examined with PET using the selective radioligands [11C]PE2I and [11C]raclopride, indexing DAT and D2R density. The simplified reference tissue model was used to calculate binding potential (BP) values. Attention and motor behavior were investigated with a continuous performance task (CPT) and motion measurements.

Results

The BP value for [11C]PE2I and [11C]raclopride in the striatum of children with ADHD did not differ from that of the young adult control subjects. In the midbrain, however, the BP values for DAT were significantly lower (16%; p = .03) in children with ADHD. Dopamine D2 receptor binding in the right caudate nucleus correlated significantly with increased motor activity (r = .70, p = .01).

Conclusions

The lower BP values for DAT in the midbrain suggest that dopamine signaling in subjects with ADHD is altered. Altered dopamine signaling might have a causal relationship to motor hyperactivity and might be considered as a potential endophenotype of ADHD.

Section snippets

Subjects

The study was approved by the Research Ethics and Radiation Safety Committees of the Karolinska Hospital. Participation in the study was voluntary, and the subjects agreed to participate after receiving written and oral information. Written informed consent was obtained from the subjects and/or their parents in accordance with the Declaration of Helsinki. The study was carried out at the PET Centre, Department of Clinical Neuroscience, Karolinska Institutet (Stockholm, Sweden).

The comparison

Dopamine transporter binding

In all subjects, the [11C]PE2I binding was highest in the striatum (caudate nucleus and putamen), lower in the midbrain (substantia nigra/ventral tegmentum), and lowest in the cerebellum (Figure 1, Figure 2). In this limited series of subjects covering a narrow age range, no significant age effect was found for [11C]PE2I binding in the striatum in any of the groups. There was, however, a tendency for DAT binding in the caudate nucleus to decrease in the adult group (regression coefficient R =

Discussion

The main results of this PET study were as follows: 1) no support for an increase in the DAT or D2R marker density in the striatum of adolescents with ADHD; 2) lower binding to DAT in the midbrain of adolescents with ADHD; and 3) statistically significant correlations between DAT and D2R binding in the striatum and measures of hyperactivity.

The mean DAT and D2R binding potential in the striatum of adolescents with ADHD was 4% and 6% higher, respectively, than the corresponding values for young

References (74)

  • A.A. Lammertsma et al.

    Simplified reference tissue model for PET receptor studies

    Neuroimage

    (1996)
  • D. Leo et al.

    Altered midbrain dopaminergic neurotransmission during development in an animal model of ADHD

    Neurosci Biobehav Rev

    (2003)
  • S.Z. Meng et al.

    Developmental and age-related changes of dopamine transporter, and dopamine D1 and D2 receptors in human basal ganglia

    Brain Res

    (1999)
  • G.W. Miller et al.

    Dopamine transporters and neuronal injury

    Trends Pharmacol Sci

    (1999)
  • S.R. Pliszka et al.

    Catholamines in attention-deficit hyperactivity disorderCurrent perspectives

    J Am Acad Child Adolesc Psychiatry

    (1996)
  • V.A. Russell

    Hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder-the spontaneously hypertensive rat

    Behav Brain Res

    (2002)
  • M. Sohmiya et al.

    Age-related structural changes in the human midbrainAn MR image study

    Neurobiol Aging

    (2001)
  • M.V. Solanto

    Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorderA review and integration

    Behav Brain Res

    (1998)
  • J.M. Swanson et al.

    Attention deficit disorder and hyperkinetic disorder

    Lancet

    (1998)
  • M.H. Teicher et al.

    Objective measurement of hyperactivity and attentional problems in ADHD

    J Am Acad Child Adolesc Psychiatry

    (1996)
  • C.H. van Dyck et al.

    Age-related decline in dopamine transportersAnalysis of striatal subregions, nonlinear effects, and hemispheric asymmetries

    Am J Geriatr Psychiatry

    (2002)
  • I.D. Waldman et al.

    Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in childrenHeterogeneity owing to diagnostic subtype and severity

    Am J Hum Genet

    (1998)
  • A. Antonini et al.

    Dopamine D2 receptors in normal human brainEffect of age measured by positron emission tomography (PET) and [11C]-raclopride

    Ann N Y Acad Sci

    (1993)
  • Diagnostic and Statistical Manual of Mental Disorders,

    (1994)
  • M.J. Bannon et al.

    Age-related and regional differences in dopamine transporter mRNA expression in human midbrain

    Neurology

    (1997)
  • M. Bergström et al.

    Head fixation device for reproducible position alignment in transmission CT and positron emission tomography

    J Comput Assist Tomogr

    (1981)
  • R.D. Blakely

    Dopamine’s reversal of fortune

    Science

    (2001)
  • C.L. Brandon et al.

    Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum

    Eur J Neurosci

    (2003)
  • R.A. Brumback et al.

    A hypothesis regarding the commonality of right-hemisphere involvement in learning disability, attentional disorder, and childhood major depressive disorder

    Percept Mot Skills

    (1982)
  • B.J. Casey

    Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder

    J Am Acad Child Adolesc Psychiatry

    (1997)
  • F.X. Castellanos et al.

    Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder

    Arch Gen Psychiatry

    (1996)
  • F.X. Castellanos et al.

    Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder

    JAMA

    (2002)
  • F.X. Castellanos et al.

    Anatomic brain abnormalities in monozygotic twins discordant for attention deficit hyperactivity disorder

    Am J Psychiatry

    (2003)
  • F.X. Castellanos et al.

    Neuroscience of attention-deficit/hyperactivity disorderThe search for endophenotypes

    Nat Rev Neurosci

    (2002)
  • S. Chalon et al.

    Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4’-methylphenyl)nortropane as a selective and potent inhibitor of the neuronal dopamine transporter

    J Pharmacol Exp Ther

    (1999)
  • K.A. Cheon et al.

    Dopamine transporter density in the basal ganglia assessed with [(123)I]IPT SPET in children with attention deficit hyperactivity disorder

    Eur J Nucl Med Mol Imaging

    (2003)
  • B.J. Ciliax et al.

    The dopamine transporterImmunochemical characterization and localization in brain

    J Neurosci

    (1995)
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