Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex

Autores
Ferreri, Maria Celeste; Gutiérrez, María Laura; Gravielle, Maria Clara
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The clinical use of benzodiazepines is limited by the development of tolerance to their pharmacological effects. Tolerance to each of the pharmacological actions of benzodiazepines develops at different rates. The aim of this work was to investigate the mechanism of tolerance by performing behavioral tests in combination with biochemical studies. To this end, we administered prolonged treatments of diazepam to rats for 7 or 14days. Tolerance to the sedative effects of diazepam was detected by means of the open field test after the 7- and 14-day treatments, whereas tolerance to the anxiolytic actions of benzodiazepine manifested following only the 14-day treatment in the elevated plus maze. The cerebral cortical concentrations of diazepam did not decline after the diazepam treatments, indicating that tolerance was not due to alterations in pharmacokinetic factors. The uncoupling of GABA/benzodiazepine site interactions and an increase in the degree of phosphorylation of the GABAA receptor γ2 subunit at serine 327 in the cerebral cortex were produced by day 7 of diazepam treatment and persisted after 14days of exposure to benzodiazepine. Thus, these alterations could be part of the mechanism of tolerance to the sedative effects of diazepam. An increase in the percentage of α1-containing GABAA receptors in the cerebral cortex was observed following the 14-day treatment with diazepam but not the 7-day treatment, suggesting that tolerance to the anxiolytic effects is associated with a change in receptor subunit composition. The understanding of the molecular bases of tolerance could be important for the development of new drugs that maintain their efficacies over long-term treatments.
Fil: Ferreri, Maria Celeste. 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: Gutiérrez, María Laura. 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
Materia
Benzodiazepine
Gaba
Gabaa Receptor
Tolerance
Uncoupling
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/38838
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/38838
network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortexFerreri, Maria CelesteGutiérrez, María LauraGravielle, Maria ClaraBenzodiazepineGabaGabaa ReceptorToleranceUncouplinghttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The clinical use of benzodiazepines is limited by the development of tolerance to their pharmacological effects. Tolerance to each of the pharmacological actions of benzodiazepines develops at different rates. The aim of this work was to investigate the mechanism of tolerance by performing behavioral tests in combination with biochemical studies. To this end, we administered prolonged treatments of diazepam to rats for 7 or 14days. Tolerance to the sedative effects of diazepam was detected by means of the open field test after the 7- and 14-day treatments, whereas tolerance to the anxiolytic actions of benzodiazepine manifested following only the 14-day treatment in the elevated plus maze. The cerebral cortical concentrations of diazepam did not decline after the diazepam treatments, indicating that tolerance was not due to alterations in pharmacokinetic factors. The uncoupling of GABA/benzodiazepine site interactions and an increase in the degree of phosphorylation of the GABAA receptor γ2 subunit at serine 327 in the cerebral cortex were produced by day 7 of diazepam treatment and persisted after 14days of exposure to benzodiazepine. Thus, these alterations could be part of the mechanism of tolerance to the sedative effects of diazepam. An increase in the percentage of α1-containing GABAA receptors in the cerebral cortex was observed following the 14-day treatment with diazepam but not the 7-day treatment, suggesting that tolerance to the anxiolytic effects is associated with a change in receptor subunit composition. The understanding of the molecular bases of tolerance could be important for the development of new drugs that maintain their efficacies over long-term treatments.Fil: Ferreri, Maria Celeste. 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: Gutiérrez, María Laura. 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; ArgentinaPergamon-Elsevier Science Ltd2015-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/38838Ferreri, Maria Celeste; Gutiérrez, María Laura; Gravielle, Maria Clara; Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex; Pergamon-Elsevier Science Ltd; Neuroscience; 310; 12-2015; 152-1620306-4522CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuroscience.2015.09.038info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S030645221500857Xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:35:14Zoai:ri.conicet.gov.ar:11336/38838instacron: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 09:35:14.291CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex
title Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex
spellingShingle Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex
Ferreri, Maria Celeste
Benzodiazepine
Gaba
Gabaa Receptor
Tolerance
Uncoupling
title_short Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex
title_full Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex
title_fullStr Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex
title_full_unstemmed Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex
title_sort Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex
dc.creator.none.fl_str_mv Ferreri, Maria Celeste
Gutiérrez, María Laura
Gravielle, Maria Clara
author Ferreri, Maria Celeste
author_facet Ferreri, Maria Celeste
Gutiérrez, María Laura
Gravielle, Maria Clara
author_role author
author2 Gutiérrez, María Laura
Gravielle, Maria Clara
author2_role author
author
dc.subject.none.fl_str_mv Benzodiazepine
Gaba
Gabaa Receptor
Tolerance
Uncoupling
topic Benzodiazepine
Gaba
Gabaa Receptor
Tolerance
Uncoupling
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 clinical use of benzodiazepines is limited by the development of tolerance to their pharmacological effects. Tolerance to each of the pharmacological actions of benzodiazepines develops at different rates. The aim of this work was to investigate the mechanism of tolerance by performing behavioral tests in combination with biochemical studies. To this end, we administered prolonged treatments of diazepam to rats for 7 or 14days. Tolerance to the sedative effects of diazepam was detected by means of the open field test after the 7- and 14-day treatments, whereas tolerance to the anxiolytic actions of benzodiazepine manifested following only the 14-day treatment in the elevated plus maze. The cerebral cortical concentrations of diazepam did not decline after the diazepam treatments, indicating that tolerance was not due to alterations in pharmacokinetic factors. The uncoupling of GABA/benzodiazepine site interactions and an increase in the degree of phosphorylation of the GABAA receptor γ2 subunit at serine 327 in the cerebral cortex were produced by day 7 of diazepam treatment and persisted after 14days of exposure to benzodiazepine. Thus, these alterations could be part of the mechanism of tolerance to the sedative effects of diazepam. An increase in the percentage of α1-containing GABAA receptors in the cerebral cortex was observed following the 14-day treatment with diazepam but not the 7-day treatment, suggesting that tolerance to the anxiolytic effects is associated with a change in receptor subunit composition. The understanding of the molecular bases of tolerance could be important for the development of new drugs that maintain their efficacies over long-term treatments.
Fil: Ferreri, Maria Celeste. 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: Gutiérrez, María Laura. 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
description The clinical use of benzodiazepines is limited by the development of tolerance to their pharmacological effects. Tolerance to each of the pharmacological actions of benzodiazepines develops at different rates. The aim of this work was to investigate the mechanism of tolerance by performing behavioral tests in combination with biochemical studies. To this end, we administered prolonged treatments of diazepam to rats for 7 or 14days. Tolerance to the sedative effects of diazepam was detected by means of the open field test after the 7- and 14-day treatments, whereas tolerance to the anxiolytic actions of benzodiazepine manifested following only the 14-day treatment in the elevated plus maze. The cerebral cortical concentrations of diazepam did not decline after the diazepam treatments, indicating that tolerance was not due to alterations in pharmacokinetic factors. The uncoupling of GABA/benzodiazepine site interactions and an increase in the degree of phosphorylation of the GABAA receptor γ2 subunit at serine 327 in the cerebral cortex were produced by day 7 of diazepam treatment and persisted after 14days of exposure to benzodiazepine. Thus, these alterations could be part of the mechanism of tolerance to the sedative effects of diazepam. An increase in the percentage of α1-containing GABAA receptors in the cerebral cortex was observed following the 14-day treatment with diazepam but not the 7-day treatment, suggesting that tolerance to the anxiolytic effects is associated with a change in receptor subunit composition. The understanding of the molecular bases of tolerance could be important for the development of new drugs that maintain their efficacies over long-term treatments.
publishDate 2015
dc.date.none.fl_str_mv 2015-12
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/11336/38838
Ferreri, Maria Celeste; Gutiérrez, María Laura; Gravielle, Maria Clara; Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex; Pergamon-Elsevier Science Ltd; Neuroscience; 310; 12-2015; 152-162
0306-4522
CONICET Digital
CONICET
url http://hdl.handle.net/11336/38838
identifier_str_mv Ferreri, Maria Celeste; Gutiérrez, María Laura; Gravielle, Maria Clara; Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex; Pergamon-Elsevier Science Ltd; Neuroscience; 310; 12-2015; 152-162
0306-4522
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuroscience.2015.09.038
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S030645221500857X
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
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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