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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.

Registro:

Documento: Artículo
Título:The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder
Autor:Avale, M.E.; Falzone, T.L.; Gelman, D.M.; Low, M.J.; Grandy, D.K.; Rubinstein, M.
Filiación:Inst. Invest. Ing. Genet. Y Biol. M., Depto. Fisiol., Biol. Molec. Y Cel., Universidad de Buenos Aires, Vuelta de Obligado, Buenos Aires, Argentina
Vollum Institute, Dept. of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, United States
Dept. of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, United States
Ctro. de Estudios Científicos, Valdivia, Chile
INGEBI-CONICET, Vuelta de Obligado 2490, 1428-Buenos Aires, Argentina
Palabras clave:6-hydroxydopamine; ADHD; Amphetamine; D4R knockout mouse; Methylphenidate; amphetamine; dopamine; dopamine 4 receptor; dopamine receptor blocking agent; methylphenidate; oxidopamine; sonepiprazole; animal experiment; animal model; article; attention deficit disorder; avoidance behavior; controlled study; dopaminergic system; female; genotype; male; maze test; mesencephalon; motor coordination; mouse; nonhuman; open field behavior; phenotype; priority journal; puberty; signal transduction; striate cortex
Año:2004
Volumen:9
Número:7
Página de inicio:718
Página de fin:726
DOI: http://dx.doi.org/10.1038/sj.mp.4001474
Título revista:Molecular Psychiatry
Título revista abreviado:Mol. Psychiatry
ISSN:13594184
CODEN:MOPSF
CAS:amphetamine, 1200-47-1, 139-10-6, 156-34-3, 2706-50-5, 300-62-9, 51-62-7, 60-13-9, 60-15-1; dopamine, 51-61-6, 62-31-7; dopamine 4 receptor, 137750-34-6; methylphenidate, 113-45-1, 298-59-9; oxidopamine, 1199-18-4, 28094-15-7, 636-00-0; sonepiprazole, 170858-33-0
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13594184_v9_n7_p718_Avale

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Citas:

---------- APA ----------
Avale, M.E., Falzone, T.L., Gelman, D.M., Low, M.J., Grandy, D.K. & Rubinstein, M. (2004) . The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder. Molecular Psychiatry, 9(7), 718-726.
http://dx.doi.org/10.1038/sj.mp.4001474
---------- CHICAGO ----------
Avale, M.E., Falzone, T.L., Gelman, D.M., Low, M.J., Grandy, D.K., Rubinstein, M. "The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder" . Molecular Psychiatry 9, no. 7 (2004) : 718-726.
http://dx.doi.org/10.1038/sj.mp.4001474
---------- MLA ----------
Avale, M.E., Falzone, T.L., Gelman, D.M., Low, M.J., Grandy, D.K., Rubinstein, M. "The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder" . Molecular Psychiatry, vol. 9, no. 7, 2004, pp. 718-726.
http://dx.doi.org/10.1038/sj.mp.4001474
---------- VANCOUVER ----------
Avale, M.E., Falzone, T.L., Gelman, D.M., Low, M.J., Grandy, D.K., Rubinstein, M. The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder. Mol. Psychiatry. 2004;9(7):718-726.
http://dx.doi.org/10.1038/sj.mp.4001474