Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear

Autores
Falzone, Tomas Luis; Gelman, Diego Matias; Young, Juan I.; Grandy, David K.; Low, Malcolm J.; Rubinstein, Marcelo
Año de publicación
2002
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The prefrontal cortex receives a major dopaminergic input from the ventral tegmental area, which plays an important role in the integration of neuronal signals influencing behavioural responses to stressful environmental stimuli. The dopamine D4 receptor (D4R) is expressed at highest levels in the prefrontal cortex and is the predominant D2-like receptor localized in this brain area. To investigate the functional significance of D4Rs in dopamine-mediated responses we have analysed a strain of mice lacking this receptor subtype (Drd4-/-). Wild-type and Drd4-/- mice were challenged in two different approach/avoidance conflict paradigms: the elevated plus maze and the light/dark preference exploration test. By these behavioural measures Drd4-/- mice showed heightened avoidance to the more fear-provoking areas of each maze as demonstrated by reduced exploration of the open arms of the plus maze and longer latencies to explore the illuminated compartment of the light/dark shuttle box. These exaggerated avoidance behaviours were further enhanced by an additional handling stress but completely prevented by anxiolytic agents such as the benzodiazepine midazolam and ethanol. Although Drd4-/- mice displayed heightened anxiety, they exhibited normal ethanol preference and consumption in a two-bottle choice test. Learned fear responses evaluated by contextual, cued and instrumental fear-conditioning tests showed no difference between wild-type and Drd4-/- mice. Taken together these results indicate that the absence of D4Rs increases avoidance behaviour to unconditioned stimuli and does not impair behavioural reactions to Pavlovian fear-conditioning, suggesting that the D4R could play a key role in the dopaminergic modulation of cortical signals triggered by environmental stimuli.
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
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
Fil: Young, Juan I.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Grandy, David K.. Oregon Health Sciences University; Estados Unidos
Fil: Low, Malcolm J.. Oregon Health Sciences 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
Materia
Anxiety
Dopamine Receptors
Fear
Frontal Cortex
Knockout Mice
Mouse
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:11336/79336
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/79336
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fearFalzone, Tomas LuisGelman, Diego MatiasYoung, Juan I.Grandy, David K.Low, Malcolm J.Rubinstein, MarceloAnxietyDopamine ReceptorsFearFrontal CortexKnockout MiceMousehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The prefrontal cortex receives a major dopaminergic input from the ventral tegmental area, which plays an important role in the integration of neuronal signals influencing behavioural responses to stressful environmental stimuli. The dopamine D4 receptor (D4R) is expressed at highest levels in the prefrontal cortex and is the predominant D2-like receptor localized in this brain area. To investigate the functional significance of D4Rs in dopamine-mediated responses we have analysed a strain of mice lacking this receptor subtype (Drd4-/-). Wild-type and Drd4-/- mice were challenged in two different approach/avoidance conflict paradigms: the elevated plus maze and the light/dark preference exploration test. By these behavioural measures Drd4-/- mice showed heightened avoidance to the more fear-provoking areas of each maze as demonstrated by reduced exploration of the open arms of the plus maze and longer latencies to explore the illuminated compartment of the light/dark shuttle box. These exaggerated avoidance behaviours were further enhanced by an additional handling stress but completely prevented by anxiolytic agents such as the benzodiazepine midazolam and ethanol. Although Drd4-/- mice displayed heightened anxiety, they exhibited normal ethanol preference and consumption in a two-bottle choice test. Learned fear responses evaluated by contextual, cued and instrumental fear-conditioning tests showed no difference between wild-type and Drd4-/- mice. Taken together these results indicate that the absence of D4Rs increases avoidance behaviour to unconditioned stimuli and does not impair behavioural reactions to Pavlovian fear-conditioning, suggesting that the D4R could play a key role in the dopaminergic modulation of cortical signals triggered by environmental stimuli.Fil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Gelman, Diego Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Young, Juan I.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Grandy, David K.. Oregon Health Sciences University; Estados UnidosFil: Low, Malcolm J.. Oregon Health Sciences 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"; ArgentinaWiley Blackwell Publishing, Inc2002-01info: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/11336/79336Falzone, Tomas Luis; Gelman, Diego Matias; Young, Juan I.; Grandy, David K.; Low, Malcolm J.; et al.; Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear; Wiley Blackwell Publishing, Inc; European Journal Of Neuroscience; 15; 1; 1-2002; 158-1640953-816XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1046/j.0953-816x.2001.01842.xinfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1046/j.0953-816x.2001.01842.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 Técnicas2025-09-29T09:50:19Zoai:ri.conicet.gov.ar:11336/79336instacron: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 09:50:19.561CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
title Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
spellingShingle Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
Falzone, Tomas Luis
Anxiety
Dopamine Receptors
Fear
Frontal Cortex
Knockout Mice
Mouse
title_short Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
title_full Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
title_fullStr Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
title_full_unstemmed Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
title_sort Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
dc.creator.none.fl_str_mv Falzone, Tomas Luis
Gelman, Diego Matias
Young, Juan I.
Grandy, David K.
Low, Malcolm J.
Rubinstein, Marcelo
author Falzone, Tomas Luis
author_facet Falzone, Tomas Luis
Gelman, Diego Matias
Young, Juan I.
Grandy, David K.
Low, Malcolm J.
Rubinstein, Marcelo
author_role author
author2 Gelman, Diego Matias
Young, Juan I.
Grandy, David K.
Low, Malcolm J.
Rubinstein, Marcelo
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Anxiety
Dopamine Receptors
Fear
Frontal Cortex
Knockout Mice
Mouse
topic Anxiety
Dopamine Receptors
Fear
Frontal Cortex
Knockout Mice
Mouse
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 prefrontal cortex receives a major dopaminergic input from the ventral tegmental area, which plays an important role in the integration of neuronal signals influencing behavioural responses to stressful environmental stimuli. The dopamine D4 receptor (D4R) is expressed at highest levels in the prefrontal cortex and is the predominant D2-like receptor localized in this brain area. To investigate the functional significance of D4Rs in dopamine-mediated responses we have analysed a strain of mice lacking this receptor subtype (Drd4-/-). Wild-type and Drd4-/- mice were challenged in two different approach/avoidance conflict paradigms: the elevated plus maze and the light/dark preference exploration test. By these behavioural measures Drd4-/- mice showed heightened avoidance to the more fear-provoking areas of each maze as demonstrated by reduced exploration of the open arms of the plus maze and longer latencies to explore the illuminated compartment of the light/dark shuttle box. These exaggerated avoidance behaviours were further enhanced by an additional handling stress but completely prevented by anxiolytic agents such as the benzodiazepine midazolam and ethanol. Although Drd4-/- mice displayed heightened anxiety, they exhibited normal ethanol preference and consumption in a two-bottle choice test. Learned fear responses evaluated by contextual, cued and instrumental fear-conditioning tests showed no difference between wild-type and Drd4-/- mice. Taken together these results indicate that the absence of D4Rs increases avoidance behaviour to unconditioned stimuli and does not impair behavioural reactions to Pavlovian fear-conditioning, suggesting that the D4R could play a key role in the dopaminergic modulation of cortical signals triggered by environmental stimuli.
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
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
Fil: Young, Juan I.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Grandy, David K.. Oregon Health Sciences University; Estados Unidos
Fil: Low, Malcolm J.. Oregon Health Sciences 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
description The prefrontal cortex receives a major dopaminergic input from the ventral tegmental area, which plays an important role in the integration of neuronal signals influencing behavioural responses to stressful environmental stimuli. The dopamine D4 receptor (D4R) is expressed at highest levels in the prefrontal cortex and is the predominant D2-like receptor localized in this brain area. To investigate the functional significance of D4Rs in dopamine-mediated responses we have analysed a strain of mice lacking this receptor subtype (Drd4-/-). Wild-type and Drd4-/- mice were challenged in two different approach/avoidance conflict paradigms: the elevated plus maze and the light/dark preference exploration test. By these behavioural measures Drd4-/- mice showed heightened avoidance to the more fear-provoking areas of each maze as demonstrated by reduced exploration of the open arms of the plus maze and longer latencies to explore the illuminated compartment of the light/dark shuttle box. These exaggerated avoidance behaviours were further enhanced by an additional handling stress but completely prevented by anxiolytic agents such as the benzodiazepine midazolam and ethanol. Although Drd4-/- mice displayed heightened anxiety, they exhibited normal ethanol preference and consumption in a two-bottle choice test. Learned fear responses evaluated by contextual, cued and instrumental fear-conditioning tests showed no difference between wild-type and Drd4-/- mice. Taken together these results indicate that the absence of D4Rs increases avoidance behaviour to unconditioned stimuli and does not impair behavioural reactions to Pavlovian fear-conditioning, suggesting that the D4R could play a key role in the dopaminergic modulation of cortical signals triggered by environmental stimuli.
publishDate 2002
dc.date.none.fl_str_mv 2002-01
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/11336/79336
Falzone, Tomas Luis; Gelman, Diego Matias; Young, Juan I.; Grandy, David K.; Low, Malcolm J.; et al.; Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear; Wiley Blackwell Publishing, Inc; European Journal Of Neuroscience; 15; 1; 1-2002; 158-164
0953-816X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/79336
identifier_str_mv Falzone, Tomas Luis; Gelman, Diego Matias; Young, Juan I.; Grandy, David K.; Low, Malcolm J.; et al.; Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear; Wiley Blackwell Publishing, Inc; European Journal Of Neuroscience; 15; 1; 1-2002; 158-164
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/10.1046/j.0953-816x.2001.01842.x
info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1046/j.0953-816x.2001.01842.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
application/pdf
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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