Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons

Autores
Medina, Nelsy Beatriz; Foitzick, María Florencia; Iglesias García, Lucía Candela; Gravielle, Maria Clara
Año de publicación
2019
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
GABA-A receptors are targets of different pharmacologically relevant drugs, such as barbiturates, benzodiazepines, and anesthetics. In particular, benzodiazepines are prescribed for the treatment of anxiety, sleep disorders, and seizure disorders. Prolonged activation of GABA-A receptors by endogenous and exogenous modulators induces adaptive changes that lead to tolerance. For example, chronic administration of benzodiazepines produces tolerance to most of their pharmacological actions, limiting their usefulness. The mechanism of tolerance is still unknown. We have previously demonstrated that chronic diazepam administration in rats result in tolerance to the sedative and anxiolytic effects which is accompanied with a decrease in the interactions between GABA and benzodizepine binding sites (uncoupling) in cerebral cortex. The aim of this work was to investigate the molecular mechanism of benzodiazepine tolerance in an in vitro model of primary neuronal cultures from rat cerebral cortex. The exposure of cultured neurons to diazepam for 48 h produced a 40 % uncoupling (p<0.05) which was prevented in the presence of nifedipine, an inhibitor of L-type voltage-gated calcium channels (L-VGCCs). Benzodiazepine treatment also induced a 45 % decrease (p<0.05) in GABA-A receptor alpha1 subunit mRNA levels (p<0.05) that was inhibited by nifedipine. We hypothesized that the adaptive changes of GABA-A receptors induced by sustained exposure to benzodiazepine are mediated by a signaling pathway that involves activation of L-VGCCs. Results from calcium mobilization and nuclear run-on assays suggested that benzodiazepine exposure produces an increase in the calcium influx through L-VGCCs that activates an intracellular signaling cascade finally leading to the transcriptional repression of alpha1 subunit gene expression. Insights into the mechanism of benzodiazepine tolerance will contribute to the design of new drugs that can maintain their efficacies after long term treatments.
Fil: Medina, Nelsy Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Foitzick, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Iglesias García, Lucía Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Gravielle, Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
Mar del Plara
Argentina
Sociedad Argentina de Investigaciones Clínicas
Asociación Argentina de Farmacología Experimental
Sociedad Argentina de Biología
Sociedad Argentina de Protozoología
Asociación Argentina de Nanomedicinas
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
Materia
GABA
BENZODIACEPINAS
TOLERANCIA
RECEPTOR GABAA
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:11336/196720
Acceder
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spelling Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neuronsMedina, Nelsy BeatrizFoitzick, María FlorenciaIglesias García, Lucía CandelaGravielle, Maria ClaraGABABENZODIACEPINASTOLERANCIARECEPTOR GABAAhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1GABA-A receptors are targets of different pharmacologically relevant drugs, such as barbiturates, benzodiazepines, and anesthetics. In particular, benzodiazepines are prescribed for the treatment of anxiety, sleep disorders, and seizure disorders. Prolonged activation of GABA-A receptors by endogenous and exogenous modulators induces adaptive changes that lead to tolerance. For example, chronic administration of benzodiazepines produces tolerance to most of their pharmacological actions, limiting their usefulness. The mechanism of tolerance is still unknown. We have previously demonstrated that chronic diazepam administration in rats result in tolerance to the sedative and anxiolytic effects which is accompanied with a decrease in the interactions between GABA and benzodizepine binding sites (uncoupling) in cerebral cortex. The aim of this work was to investigate the molecular mechanism of benzodiazepine tolerance in an in vitro model of primary neuronal cultures from rat cerebral cortex. The exposure of cultured neurons to diazepam for 48 h produced a 40 % uncoupling (p<0.05) which was prevented in the presence of nifedipine, an inhibitor of L-type voltage-gated calcium channels (L-VGCCs). Benzodiazepine treatment also induced a 45 % decrease (p<0.05) in GABA-A receptor alpha1 subunit mRNA levels (p<0.05) that was inhibited by nifedipine. We hypothesized that the adaptive changes of GABA-A receptors induced by sustained exposure to benzodiazepine are mediated by a signaling pathway that involves activation of L-VGCCs. Results from calcium mobilization and nuclear run-on assays suggested that benzodiazepine exposure produces an increase in the calcium influx through L-VGCCs that activates an intracellular signaling cascade finally leading to the transcriptional repression of alpha1 subunit gene expression. Insights into the mechanism of benzodiazepine tolerance will contribute to the design of new drugs that can maintain their efficacies after long term treatments.Fil: Medina, Nelsy Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Foitzick, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Iglesias García, Lucía Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Gravielle, Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaLXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de LaboratorioMar del PlaraArgentinaSociedad Argentina de Investigaciones ClínicasAsociación Argentina de Farmacología ExperimentalSociedad Argentina de BiologíaSociedad Argentina de ProtozoologíaAsociación Argentina de NanomedicinasAsociación Argentina de Ciencia y Tecnología de Animales de LaboratorioFundación Revista Medicina2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/196720Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio; Mar del Plara; Argentina; 2019; 270-2700025-7680CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.saic.org.ar/reunion-anualNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:05:24Zoai:ri.conicet.gov.ar:11336/196720instacron: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 10:05:24.715CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons
title Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons
spellingShingle Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons
Medina, Nelsy Beatriz
GABA
BENZODIACEPINAS
TOLERANCIA
RECEPTOR GABAA
title_short Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons
title_full Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons
title_fullStr Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons
title_full_unstemmed Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons
title_sort Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons
dc.creator.none.fl_str_mv Medina, Nelsy Beatriz
Foitzick, María Florencia
Iglesias García, Lucía Candela
Gravielle, Maria Clara
author Medina, Nelsy Beatriz
author_facet Medina, Nelsy Beatriz
Foitzick, María Florencia
Iglesias García, Lucía Candela
Gravielle, Maria Clara
author_role author
author2 Foitzick, María Florencia
Iglesias García, Lucía Candela
Gravielle, Maria Clara
author2_role author
author
author
dc.subject.none.fl_str_mv GABA
BENZODIACEPINAS
TOLERANCIA
RECEPTOR GABAA
topic GABA
BENZODIACEPINAS
TOLERANCIA
RECEPTOR GABAA
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv GABA-A receptors are targets of different pharmacologically relevant drugs, such as barbiturates, benzodiazepines, and anesthetics. In particular, benzodiazepines are prescribed for the treatment of anxiety, sleep disorders, and seizure disorders. Prolonged activation of GABA-A receptors by endogenous and exogenous modulators induces adaptive changes that lead to tolerance. For example, chronic administration of benzodiazepines produces tolerance to most of their pharmacological actions, limiting their usefulness. The mechanism of tolerance is still unknown. We have previously demonstrated that chronic diazepam administration in rats result in tolerance to the sedative and anxiolytic effects which is accompanied with a decrease in the interactions between GABA and benzodizepine binding sites (uncoupling) in cerebral cortex. The aim of this work was to investigate the molecular mechanism of benzodiazepine tolerance in an in vitro model of primary neuronal cultures from rat cerebral cortex. The exposure of cultured neurons to diazepam for 48 h produced a 40 % uncoupling (p<0.05) which was prevented in the presence of nifedipine, an inhibitor of L-type voltage-gated calcium channels (L-VGCCs). Benzodiazepine treatment also induced a 45 % decrease (p<0.05) in GABA-A receptor alpha1 subunit mRNA levels (p<0.05) that was inhibited by nifedipine. We hypothesized that the adaptive changes of GABA-A receptors induced by sustained exposure to benzodiazepine are mediated by a signaling pathway that involves activation of L-VGCCs. Results from calcium mobilization and nuclear run-on assays suggested that benzodiazepine exposure produces an increase in the calcium influx through L-VGCCs that activates an intracellular signaling cascade finally leading to the transcriptional repression of alpha1 subunit gene expression. Insights into the mechanism of benzodiazepine tolerance will contribute to the design of new drugs that can maintain their efficacies after long term treatments.
Fil: Medina, Nelsy Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Foitzick, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Iglesias García, Lucía Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Gravielle, Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
Mar del Plara
Argentina
Sociedad Argentina de Investigaciones Clínicas
Asociación Argentina de Farmacología Experimental
Sociedad Argentina de Biología
Sociedad Argentina de Protozoología
Asociación Argentina de Nanomedicinas
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
description GABA-A receptors are targets of different pharmacologically relevant drugs, such as barbiturates, benzodiazepines, and anesthetics. In particular, benzodiazepines are prescribed for the treatment of anxiety, sleep disorders, and seizure disorders. Prolonged activation of GABA-A receptors by endogenous and exogenous modulators induces adaptive changes that lead to tolerance. For example, chronic administration of benzodiazepines produces tolerance to most of their pharmacological actions, limiting their usefulness. The mechanism of tolerance is still unknown. We have previously demonstrated that chronic diazepam administration in rats result in tolerance to the sedative and anxiolytic effects which is accompanied with a decrease in the interactions between GABA and benzodizepine binding sites (uncoupling) in cerebral cortex. The aim of this work was to investigate the molecular mechanism of benzodiazepine tolerance in an in vitro model of primary neuronal cultures from rat cerebral cortex. The exposure of cultured neurons to diazepam for 48 h produced a 40 % uncoupling (p<0.05) which was prevented in the presence of nifedipine, an inhibitor of L-type voltage-gated calcium channels (L-VGCCs). Benzodiazepine treatment also induced a 45 % decrease (p<0.05) in GABA-A receptor alpha1 subunit mRNA levels (p<0.05) that was inhibited by nifedipine. We hypothesized that the adaptive changes of GABA-A receptors induced by sustained exposure to benzodiazepine are mediated by a signaling pathway that involves activation of L-VGCCs. Results from calcium mobilization and nuclear run-on assays suggested that benzodiazepine exposure produces an increase in the calcium influx through L-VGCCs that activates an intracellular signaling cascade finally leading to the transcriptional repression of alpha1 subunit gene expression. Insights into the mechanism of benzodiazepine tolerance will contribute to the design of new drugs that can maintain their efficacies after long term treatments.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
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Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/196720
Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio; Mar del Plara; Argentina; 2019; 270-270
0025-7680
CONICET Digital
CONICET
url http://hdl.handle.net/11336/196720
identifier_str_mv Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio; Mar del Plara; Argentina; 2019; 270-270
0025-7680
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
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