The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder

M. E. Avale, T. L. Falzone, D. M. Gelman, M. J. Low, David Grandy, M. Rubinstein

    Research output: Contribution to journalArticle

    97 Citations (Scopus)

    Abstract

    The dopamine D4 receptor (D4R) is a candidate gene for attention deficit/hyperactivity disorder (ADHD) based on genetic studies reporting that particular polymorphisms are present at a higher frequency in affected children. However, the direct participation of the D4R in the onset or progression of ADHD has not been tested. Here, we generated a mouse model with high face value to screen candidate genes for the clinical disorder by neonatal disruption of central dopaminergic pathways with 6-hydroxydopamine (6-OHDA). The lesioned mice exhibited hyperactivity that waned after puberty, paradoxical hypolocomotor responses to amphetamine and methylphenidate, poor behavioral inhibition in approach/avoidance conflict tests and deficits in continuously performed motor coordination tasks. To determine whether the D4R plays a role in these behavioral phenotypes, we performed 6-OHDA lesions in neonatal mice lacking D4Rs (Drd4-/-). Although striatal dopamine contents and tyrosine hydroxylase-positive midbrain neurons were reduced to the same extent in both genotypes, Drd4-/- mice lesioned with 6-OHDA did not develop hyperactivity. Similarly, the D4R antagonist PNU-101387G prevented hyperactivity in wild-type 6-OHDA-lesioned mice. Furthermore, wild-type mice lesioned with 6-OHDA showed an absence of behavioral inhibition when tested in the open field or the elevated plus maze, while their Drd4-/- siblings exhibited normal avoidance for the unprotected areas of these mazes. Together, our results from a combination of genetic and pharmacological approaches demonstrate that D4R signaling is essential for the expression of juvenile hyperactivity and impaired behavioral inhibition, relevant features present in this ADHD-like mouse model.

    Original languageEnglish (US)
    Pages (from-to)718-726
    Number of pages9
    JournalMolecular Psychiatry
    Volume9
    Issue number7
    StatePublished - Jul 2004

    Fingerprint

    Dopamine D4 Receptors
    Attention Deficit Disorder with Hyperactivity
    Oxidopamine
    Corpus Striatum
    Methylphenidate
    Tyrosine 3-Monooxygenase
    Amphetamine
    Puberty
    Mesencephalon
    Inhibition (Psychology)
    Genes
    Siblings
    Dopamine
    Genotype
    Pharmacology
    Phenotype
    Neurons

    Keywords

    • 6-hydroxydopamine
    • ADHD
    • Amphetamine
    • D4R knockout mouse
    • Methylphenidate

    ASJC Scopus subject areas

    • Molecular Biology
    • Psychiatry and Mental health

    Cite this

    The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder. / Avale, M. E.; Falzone, T. L.; Gelman, D. M.; Low, M. J.; Grandy, David; Rubinstein, M.

    In: Molecular Psychiatry, Vol. 9, No. 7, 07.2004, p. 718-726.

    Research output: Contribution to journalArticle

    Avale, M. E. ; Falzone, T. L. ; Gelman, D. M. ; Low, M. J. ; Grandy, David ; Rubinstein, M. / The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder. In: Molecular Psychiatry. 2004 ; Vol. 9, No. 7. pp. 718-726.
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