The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder
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...
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todo:paper_13594184_v9_n7_p718_Avale2023-10-03T16:10:34Z 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, D.K. Rubinstein, M. 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 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_13594184_v9_n7_p718_Avale |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 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 |
| topic_facet |
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 |
| description |
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. |
| format |
JOUR |
| author |
Avale, M.E. Falzone, T.L. Gelman, D.M. Low, M.J. Grandy, D.K. Rubinstein, M. |
| author_facet |
Avale, M.E. Falzone, T.L. Gelman, D.M. Low, M.J. Grandy, D.K. Rubinstein, M. |
| author_sort |
Avale, M.E. |
| title |
The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder |
| title_short |
The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder |
| title_full |
The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder |
| title_fullStr |
The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder |
| title_full_unstemmed |
The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder |
| title_sort |
dopamine d4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder |
| url |
http://hdl.handle.net/20.500.12110/paper_13594184_v9_n7_p718_Avale |
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