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

Autores
Avale, Maria Elena; Falzone, Tomas Luis; Gelman, Diego Matias; Low, Malcolm J.; Grandy, David K.; Rubinstein, Marcelo
Año de publicación
2004
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Gelman, Diego Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Low, Malcolm J.. Oregon Health and Science University; Estados Unidos
Fil: Grandy, David K.. Oregon Health and Science University; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Centro de Estudios Científicos; Chile
Materia
6-Hydroxydopamine
Adhd
Amphetamine
D4r Knockout Mouse
Methylphenidate
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/79753
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/79753
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorderAvale, Maria ElenaFalzone, Tomas LuisGelman, Diego MatiasLow, Malcolm J.Grandy, David K.Rubinstein, Marcelo6-HydroxydopamineAdhdAmphetamineD4r Knockout MouseMethylphenidatehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The 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.Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Gelman, Diego Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Low, Malcolm J.. Oregon Health and Science University; Estados UnidosFil: Grandy, David K.. Oregon Health and Science University; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Centro de Estudios Científicos; ChileNature Publishing Group2004-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/79753Avale, Maria Elena; Falzone, Tomas Luis; Gelman, Diego Matias; Low, Malcolm J.; Grandy, David K.; et al.; The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder; Nature Publishing Group; Molecular Psychiatry; 9; 7; 7-2004; 718-7261359-4184CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/sj.mp.4001474info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pubmed/14699433info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/4001474info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:09:23Zoai:ri.conicet.gov.ar:11336/79753instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:09:24.259CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder
title The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder
spellingShingle The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder
Avale, Maria Elena
6-Hydroxydopamine
Adhd
Amphetamine
D4r Knockout Mouse
Methylphenidate
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 The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder
dc.creator.none.fl_str_mv Avale, Maria Elena
Falzone, Tomas Luis
Gelman, Diego Matias
Low, Malcolm J.
Grandy, David K.
Rubinstein, Marcelo
author Avale, Maria Elena
author_facet Avale, Maria Elena
Falzone, Tomas Luis
Gelman, Diego Matias
Low, Malcolm J.
Grandy, David K.
Rubinstein, Marcelo
author_role author
author2 Falzone, Tomas Luis
Gelman, Diego Matias
Low, Malcolm J.
Grandy, David K.
Rubinstein, Marcelo
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv 6-Hydroxydopamine
Adhd
Amphetamine
D4r Knockout Mouse
Methylphenidate
topic 6-Hydroxydopamine
Adhd
Amphetamine
D4r Knockout Mouse
Methylphenidate
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Gelman, Diego Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Low, Malcolm J.. Oregon Health and Science University; Estados Unidos
Fil: Grandy, David K.. Oregon Health and Science University; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Centro de Estudios Científicos; Chile
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.
publishDate 2004
dc.date.none.fl_str_mv 2004-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/79753
Avale, Maria Elena; Falzone, Tomas Luis; Gelman, Diego Matias; Low, Malcolm J.; Grandy, David K.; et al.; The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder; Nature Publishing Group; Molecular Psychiatry; 9; 7; 7-2004; 718-726
1359-4184
CONICET Digital
CONICET
url http://hdl.handle.net/11336/79753
identifier_str_mv Avale, Maria Elena; Falzone, Tomas Luis; Gelman, Diego Matias; Low, Malcolm J.; Grandy, David K.; et al.; The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder; Nature Publishing Group; Molecular Psychiatry; 9; 7; 7-2004; 718-726
1359-4184
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pubmed/14699433
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/4001474
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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