Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate

Autores
Michaelides, Michael; Pascau, Javier; Gispert, Juan Domingo; Delis, Foteini; Grandy, David K.; Wang, Gene Jack; Desco, Manuel; Rubinstein, Marcelo; Volkow, Nora D.; Thanos, Panayotis K.
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Methylphenidate (MP) is widely used to treat attention deficit hyperactivity disorder (ADHD). Variable number of tandem repeats polymorphisms in the dopamine D4 receptor (D4) gene have been implicated in vulnerability to ADHD and the response to MP. Here we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [18F]2-fluoro- 2-deoxy-d-glucose) at baseline and after MP (10 mg/kg, i.p.) administration in mice with genetic deletion of the D4. Images were analyzed using a novel automated image registration procedure. Baseline D4 -/- mice had lower metabolism in the prefrontal cortex (PFC) and greater metabolism in the cerebellar vermis (CBV) than D4 +/+ and D4 +/- mice; when given MP, D 4 -/- mice increased metabolism in the PFC and decreased it in the CBV, whereas in D4 +/+ and D4 +/- mice, MP decreased metabolism in the PFC and increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally expressed in this region. As individuals with ADHD show structural and/or functional abnormalities in these brain regions, the association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and between patients with ADHD with different D4 polymorphisms.
Fil: Michaelides, Michael. Brookhaven National Laboratory; Estados Unidos. Stony Brook University; Estados Unidos
Fil: Pascau, Javier. Hospital General Universitario Gregorio Marañon; España
Fil: Gispert, Juan Domingo. Institut D’Alta Tecnologia; España
Fil: Delis, Foteini. Laboratory of Neuroimaging; Estados Unidos
Fil: Grandy, David K.. Oregon Health Sciences University; Estados Unidos
Fil: Wang, Gene Jack. Laboratory of Neuroimaging; Estados Unidos
Fil: Desco, Manuel. Hospital General Universitario Gregorio Marañon; España
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Volkow, Nora D.. Laboratory of Neuroimaging; Estados Unidos
Fil: Thanos, Panayotis K.. Brookhaven National Laboratory; Estados Unidos. Institut D’Alta Tecnologia; España. Laboratory of Neuroimaging; Estados Unidos
Materia
2-[18f]-Fluoro-2-Deoxy-D-Glucose
Attention Deficit Hyperactivity Disorder
Mice
Micro-Positron Emission Tomography
Positron Emission Tomography
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:11336/79581
Acceder
id CONICETDig_569d273cced6df111333209bebbc6535
oai_identifier_str oai:ri.conicet.gov.ar:11336/79581
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidateMichaelides, MichaelPascau, JavierGispert, Juan DomingoDelis, FoteiniGrandy, David K.Wang, Gene JackDesco, ManuelRubinstein, MarceloVolkow, Nora D.Thanos, Panayotis K.2-[18f]-Fluoro-2-Deoxy-D-GlucoseAttention Deficit Hyperactivity DisorderMiceMicro-Positron Emission TomographyPositron Emission Tomographyhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Methylphenidate (MP) is widely used to treat attention deficit hyperactivity disorder (ADHD). Variable number of tandem repeats polymorphisms in the dopamine D4 receptor (D4) gene have been implicated in vulnerability to ADHD and the response to MP. Here we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [18F]2-fluoro- 2-deoxy-d-glucose) at baseline and after MP (10 mg/kg, i.p.) administration in mice with genetic deletion of the D4. Images were analyzed using a novel automated image registration procedure. Baseline D4 -/- mice had lower metabolism in the prefrontal cortex (PFC) and greater metabolism in the cerebellar vermis (CBV) than D4 +/+ and D4 +/- mice; when given MP, D 4 -/- mice increased metabolism in the PFC and decreased it in the CBV, whereas in D4 +/+ and D4 +/- mice, MP decreased metabolism in the PFC and increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally expressed in this region. As individuals with ADHD show structural and/or functional abnormalities in these brain regions, the association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and between patients with ADHD with different D4 polymorphisms.Fil: Michaelides, Michael. Brookhaven National Laboratory; Estados Unidos. Stony Brook University; Estados UnidosFil: Pascau, Javier. Hospital General Universitario Gregorio Marañon; EspañaFil: Gispert, Juan Domingo. Institut D’Alta Tecnologia; EspañaFil: Delis, Foteini. Laboratory of Neuroimaging; Estados UnidosFil: Grandy, David K.. Oregon Health Sciences University; Estados UnidosFil: Wang, Gene Jack. Laboratory of Neuroimaging; Estados UnidosFil: Desco, Manuel. Hospital General Universitario Gregorio Marañon; EspañaFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Volkow, Nora D.. Laboratory of Neuroimaging; Estados UnidosFil: Thanos, Panayotis K.. Brookhaven National Laboratory; Estados Unidos. Institut D’Alta Tecnologia; España. Laboratory of Neuroimaging; Estados UnidosWiley Blackwell Publishing, Inc2010-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/79581Michaelides, Michael; Pascau, Javier; Gispert, Juan Domingo; Delis, Foteini; Grandy, David K.; et al.; Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate; Wiley Blackwell Publishing, Inc; European Journal Of Neuroscience; 32; 4; 8-2010; 668-6760953-816XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1111/j.1460-9568.2010.07319.xinfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1460-9568.2010.07319.xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:56:47Zoai:ri.conicet.gov.ar:11336/79581instacron: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:34982025-09-29 09:56:48.0CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
title Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
spellingShingle Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
Michaelides, Michael
2-[18f]-Fluoro-2-Deoxy-D-Glucose
Attention Deficit Hyperactivity Disorder
Mice
Micro-Positron Emission Tomography
Positron Emission Tomography
title_short Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
title_full Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
title_fullStr Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
title_full_unstemmed Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
title_sort Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
dc.creator.none.fl_str_mv Michaelides, Michael
Pascau, Javier
Gispert, Juan Domingo
Delis, Foteini
Grandy, David K.
Wang, Gene Jack
Desco, Manuel
Rubinstein, Marcelo
Volkow, Nora D.
Thanos, Panayotis K.
author Michaelides, Michael
author_facet Michaelides, Michael
Pascau, Javier
Gispert, Juan Domingo
Delis, Foteini
Grandy, David K.
Wang, Gene Jack
Desco, Manuel
Rubinstein, Marcelo
Volkow, Nora D.
Thanos, Panayotis K.
author_role author
author2 Pascau, Javier
Gispert, Juan Domingo
Delis, Foteini
Grandy, David K.
Wang, Gene Jack
Desco, Manuel
Rubinstein, Marcelo
Volkow, Nora D.
Thanos, Panayotis K.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv 2-[18f]-Fluoro-2-Deoxy-D-Glucose
Attention Deficit Hyperactivity Disorder
Mice
Micro-Positron Emission Tomography
Positron Emission Tomography
topic 2-[18f]-Fluoro-2-Deoxy-D-Glucose
Attention Deficit Hyperactivity Disorder
Mice
Micro-Positron Emission Tomography
Positron Emission Tomography
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Methylphenidate (MP) is widely used to treat attention deficit hyperactivity disorder (ADHD). Variable number of tandem repeats polymorphisms in the dopamine D4 receptor (D4) gene have been implicated in vulnerability to ADHD and the response to MP. Here we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [18F]2-fluoro- 2-deoxy-d-glucose) at baseline and after MP (10 mg/kg, i.p.) administration in mice with genetic deletion of the D4. Images were analyzed using a novel automated image registration procedure. Baseline D4 -/- mice had lower metabolism in the prefrontal cortex (PFC) and greater metabolism in the cerebellar vermis (CBV) than D4 +/+ and D4 +/- mice; when given MP, D 4 -/- mice increased metabolism in the PFC and decreased it in the CBV, whereas in D4 +/+ and D4 +/- mice, MP decreased metabolism in the PFC and increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally expressed in this region. As individuals with ADHD show structural and/or functional abnormalities in these brain regions, the association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and between patients with ADHD with different D4 polymorphisms.
Fil: Michaelides, Michael. Brookhaven National Laboratory; Estados Unidos. Stony Brook University; Estados Unidos
Fil: Pascau, Javier. Hospital General Universitario Gregorio Marañon; España
Fil: Gispert, Juan Domingo. Institut D’Alta Tecnologia; España
Fil: Delis, Foteini. Laboratory of Neuroimaging; Estados Unidos
Fil: Grandy, David K.. Oregon Health Sciences University; Estados Unidos
Fil: Wang, Gene Jack. Laboratory of Neuroimaging; Estados Unidos
Fil: Desco, Manuel. Hospital General Universitario Gregorio Marañon; España
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Volkow, Nora D.. Laboratory of Neuroimaging; Estados Unidos
Fil: Thanos, Panayotis K.. Brookhaven National Laboratory; Estados Unidos. Institut D’Alta Tecnologia; España. Laboratory of Neuroimaging; Estados Unidos
description Methylphenidate (MP) is widely used to treat attention deficit hyperactivity disorder (ADHD). Variable number of tandem repeats polymorphisms in the dopamine D4 receptor (D4) gene have been implicated in vulnerability to ADHD and the response to MP. Here we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [18F]2-fluoro- 2-deoxy-d-glucose) at baseline and after MP (10 mg/kg, i.p.) administration in mice with genetic deletion of the D4. Images were analyzed using a novel automated image registration procedure. Baseline D4 -/- mice had lower metabolism in the prefrontal cortex (PFC) and greater metabolism in the cerebellar vermis (CBV) than D4 +/+ and D4 +/- mice; when given MP, D 4 -/- mice increased metabolism in the PFC and decreased it in the CBV, whereas in D4 +/+ and D4 +/- mice, MP decreased metabolism in the PFC and increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally expressed in this region. As individuals with ADHD show structural and/or functional abnormalities in these brain regions, the association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and between patients with ADHD with different D4 polymorphisms.
publishDate 2010
dc.date.none.fl_str_mv 2010-08
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/11336/79581
Michaelides, Michael; Pascau, Javier; Gispert, Juan Domingo; Delis, Foteini; Grandy, David K.; et al.; Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate; Wiley Blackwell Publishing, Inc; European Journal Of Neuroscience; 32; 4; 8-2010; 668-676
0953-816X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/79581
identifier_str_mv Michaelides, Michael; Pascau, Javier; Gispert, Juan Domingo; Delis, Foteini; Grandy, David K.; et al.; Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate; Wiley Blackwell Publishing, Inc; European Journal Of Neuroscience; 32; 4; 8-2010; 668-676
0953-816X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1111/j.1460-9568.2010.07319.x
info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1460-9568.2010.07319.x
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
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
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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score 13.070432

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