Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice

Detalhes bibliográficos
Autor(a) principal: Baptista-de-Souza, Daniela [UNESP]
Data de Publicação: 2020
Outros Autores: Tavares, Lígia Renata Rodrigues [UNESP], Furuya-da-Cunha, Elke Mayumi [UNESP], Carneiro de Oliveira, Paulo Eduardo [UNESP], Canto-de-Souza, Lucas [UNESP], Nunes-de-Souza, Ricardo Luiz [UNESP], Canto-de-Souza, Azair [UNESP]
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.3389/fphar.2020.00260
http://hdl.handle.net/11449/201659
Resumo: Growing evidence suggests an important role of fluoxetine with serotonin 5-HT1A and 5-HT2C receptors in the modulation of emotion and nociception in brain areas such as the amygdala and periaqueductal gray (PAG). Acute fluoxetine impairs 5-HT2C (but not 5-HT1A) receptor activation in the amygdaloid complex. Given that fluoxetine produces its clinical therapeutic effects only when given chronically, this study investigated the effects of chronic treatment with fluoxetine on the effects produced by 5-HT1A or 5-HT2C receptors activation in the amygdala or PAG on fear-induced antinociception. We recorded the effects of chronic fluoxetine on serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels as well as serotonin turnover; 5-HT1A and 5-HT2C receptor protein levels in the amygdala and PAG. Also, we evaluated the effects of chronic fluoxetine combined with intra-amygdala or intra-PAG injection of MK-212 (a 5-HT2C agonist; 0.63 nmol) or 8-OH-DPAT (a 5-HT1A agonist; 10 nmol) on the antinociceptive response in mice confined in the open arm of the elevated plus-maze (EPM). Nociception was assessed with the writhing test induced by intraperitoneal injection of 0.6% acetic acid. Results showed that fluoxetine (20 mg/kg, s.c.) enhanced the open-arm induced antinociception (OAA) and reduced the number of writhes in mice confined in the enclosed arm, featuring an analgesic effect. In addition, fluoxetine increased the expression of 5-HT2C receptors and 5-HT levels whereas reduced its turnover in the amygdala. While fluoxetine did not change 5-HT and 5-HIAA levels, and its turnover in the PAG, it up-regulated 5HT1A and 5-HT2C receptors in this midbrain area. Chronic fluoxetine (5.0 mg/Kg, an intrinsically inactive dose on nociception) antagonized the enhancement of OAA produced by intra-amygdala or intra-PAG injection of MK-212. Fluoxetine also impaired the attenuation of OAA induced by intra-amygdala injection of 8-OH-DPAT and totally prevented OAA in mice that received intra-PAG 8-OH-DPAT. These results suggest that (i) 5-HT may facilitate nociception and intensify OAA, acting at amygdala 5-HT1A and 5-HT2C receptors, respectively, and (ii) fluoxetine modulates the OAA through activation of 5-HT2C receptors within the PAG. These findings indicate that chronic fluoxetine impairs the effects of 5-HT1A and 5-HT2C receptors activation in the amygdala and PAG on fear-induced antinociception in mice.
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spelling Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice5-HT1A and 5HT2C receptorsamygdalaantinociceptionfluoxetinemiceperiaqueductal gray matterserotoninGrowing evidence suggests an important role of fluoxetine with serotonin 5-HT1A and 5-HT2C receptors in the modulation of emotion and nociception in brain areas such as the amygdala and periaqueductal gray (PAG). Acute fluoxetine impairs 5-HT2C (but not 5-HT1A) receptor activation in the amygdaloid complex. Given that fluoxetine produces its clinical therapeutic effects only when given chronically, this study investigated the effects of chronic treatment with fluoxetine on the effects produced by 5-HT1A or 5-HT2C receptors activation in the amygdala or PAG on fear-induced antinociception. We recorded the effects of chronic fluoxetine on serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels as well as serotonin turnover; 5-HT1A and 5-HT2C receptor protein levels in the amygdala and PAG. Also, we evaluated the effects of chronic fluoxetine combined with intra-amygdala or intra-PAG injection of MK-212 (a 5-HT2C agonist; 0.63 nmol) or 8-OH-DPAT (a 5-HT1A agonist; 10 nmol) on the antinociceptive response in mice confined in the open arm of the elevated plus-maze (EPM). Nociception was assessed with the writhing test induced by intraperitoneal injection of 0.6% acetic acid. Results showed that fluoxetine (20 mg/kg, s.c.) enhanced the open-arm induced antinociception (OAA) and reduced the number of writhes in mice confined in the enclosed arm, featuring an analgesic effect. In addition, fluoxetine increased the expression of 5-HT2C receptors and 5-HT levels whereas reduced its turnover in the amygdala. While fluoxetine did not change 5-HT and 5-HIAA levels, and its turnover in the PAG, it up-regulated 5HT1A and 5-HT2C receptors in this midbrain area. Chronic fluoxetine (5.0 mg/Kg, an intrinsically inactive dose on nociception) antagonized the enhancement of OAA produced by intra-amygdala or intra-PAG injection of MK-212. Fluoxetine also impaired the attenuation of OAA induced by intra-amygdala injection of 8-OH-DPAT and totally prevented OAA in mice that received intra-PAG 8-OH-DPAT. These results suggest that (i) 5-HT may facilitate nociception and intensify OAA, acting at amygdala 5-HT1A and 5-HT2C receptors, respectively, and (ii) fluoxetine modulates the OAA through activation of 5-HT2C receptors within the PAG. These findings indicate that chronic fluoxetine impairs the effects of 5-HT1A and 5-HT2C receptors activation in the amygdala and PAG on fear-induced antinociception in mice.Department of Psychology Federal University of São Carlos-UFSCarJoint Graduate Program in Physiological Sciences UFSCar/UNESPInstitute of Neuroscience and Behavior, Ribeirão PretoLaboratory of Pharmacology School of Pharmaceutical Sciences Univ. Estadual Paulista – UNESPGraduate Program in Psychology UFSCarJoint Graduate Program in Physiological Sciences UFSCar/UNESPLaboratory of Pharmacology School of Pharmaceutical Sciences Univ. Estadual Paulista – UNESPUniversidade Federal de São Carlos (UFSCar)Universidade Estadual Paulista (Unesp)Institute of Neuroscience and BehaviorBaptista-de-Souza, Daniela [UNESP]Tavares, Lígia Renata Rodrigues [UNESP]Furuya-da-Cunha, Elke Mayumi [UNESP]Carneiro de Oliveira, Paulo Eduardo [UNESP]Canto-de-Souza, Lucas [UNESP]Nunes-de-Souza, Ricardo Luiz [UNESP]Canto-de-Souza, Azair [UNESP]2020-12-12T02:38:27Z2020-12-12T02:38:27Z2020-03-11info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.3389/fphar.2020.00260Frontiers in Pharmacology, v. 11.1663-9812http://hdl.handle.net/11449/20165910.3389/fphar.2020.002602-s2.0-85082683042Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengFrontiers in Pharmacologyinfo:eu-repo/semantics/openAccess2024-06-24T14:52:03Zoai:repositorio.unesp.br:11449/201659Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T23:22:25.281926Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice
title Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice
spellingShingle Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice
Baptista-de-Souza, Daniela [UNESP]
5-HT1A and 5HT2C receptors
amygdala
antinociception
fluoxetine
mice
periaqueductal gray matter
serotonin
title_short Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice
title_full Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice
title_fullStr Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice
title_full_unstemmed Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice
title_sort Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice
author Baptista-de-Souza, Daniela [UNESP]
author_facet Baptista-de-Souza, Daniela [UNESP]
Tavares, Lígia Renata Rodrigues [UNESP]
Furuya-da-Cunha, Elke Mayumi [UNESP]
Carneiro de Oliveira, Paulo Eduardo [UNESP]
Canto-de-Souza, Lucas [UNESP]
Nunes-de-Souza, Ricardo Luiz [UNESP]
Canto-de-Souza, Azair [UNESP]
author_role author
author2 Tavares, Lígia Renata Rodrigues [UNESP]
Furuya-da-Cunha, Elke Mayumi [UNESP]
Carneiro de Oliveira, Paulo Eduardo [UNESP]
Canto-de-Souza, Lucas [UNESP]
Nunes-de-Souza, Ricardo Luiz [UNESP]
Canto-de-Souza, Azair [UNESP]
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade Federal de São Carlos (UFSCar)
Universidade Estadual Paulista (Unesp)
Institute of Neuroscience and Behavior
dc.contributor.author.fl_str_mv Baptista-de-Souza, Daniela [UNESP]
Tavares, Lígia Renata Rodrigues [UNESP]
Furuya-da-Cunha, Elke Mayumi [UNESP]
Carneiro de Oliveira, Paulo Eduardo [UNESP]
Canto-de-Souza, Lucas [UNESP]
Nunes-de-Souza, Ricardo Luiz [UNESP]
Canto-de-Souza, Azair [UNESP]
dc.subject.por.fl_str_mv 5-HT1A and 5HT2C receptors
amygdala
antinociception
fluoxetine
mice
periaqueductal gray matter
serotonin
topic 5-HT1A and 5HT2C receptors
amygdala
antinociception
fluoxetine
mice
periaqueductal gray matter
serotonin
description Growing evidence suggests an important role of fluoxetine with serotonin 5-HT1A and 5-HT2C receptors in the modulation of emotion and nociception in brain areas such as the amygdala and periaqueductal gray (PAG). Acute fluoxetine impairs 5-HT2C (but not 5-HT1A) receptor activation in the amygdaloid complex. Given that fluoxetine produces its clinical therapeutic effects only when given chronically, this study investigated the effects of chronic treatment with fluoxetine on the effects produced by 5-HT1A or 5-HT2C receptors activation in the amygdala or PAG on fear-induced antinociception. We recorded the effects of chronic fluoxetine on serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels as well as serotonin turnover; 5-HT1A and 5-HT2C receptor protein levels in the amygdala and PAG. Also, we evaluated the effects of chronic fluoxetine combined with intra-amygdala or intra-PAG injection of MK-212 (a 5-HT2C agonist; 0.63 nmol) or 8-OH-DPAT (a 5-HT1A agonist; 10 nmol) on the antinociceptive response in mice confined in the open arm of the elevated plus-maze (EPM). Nociception was assessed with the writhing test induced by intraperitoneal injection of 0.6% acetic acid. Results showed that fluoxetine (20 mg/kg, s.c.) enhanced the open-arm induced antinociception (OAA) and reduced the number of writhes in mice confined in the enclosed arm, featuring an analgesic effect. In addition, fluoxetine increased the expression of 5-HT2C receptors and 5-HT levels whereas reduced its turnover in the amygdala. While fluoxetine did not change 5-HT and 5-HIAA levels, and its turnover in the PAG, it up-regulated 5HT1A and 5-HT2C receptors in this midbrain area. Chronic fluoxetine (5.0 mg/Kg, an intrinsically inactive dose on nociception) antagonized the enhancement of OAA produced by intra-amygdala or intra-PAG injection of MK-212. Fluoxetine also impaired the attenuation of OAA induced by intra-amygdala injection of 8-OH-DPAT and totally prevented OAA in mice that received intra-PAG 8-OH-DPAT. These results suggest that (i) 5-HT may facilitate nociception and intensify OAA, acting at amygdala 5-HT1A and 5-HT2C receptors, respectively, and (ii) fluoxetine modulates the OAA through activation of 5-HT2C receptors within the PAG. These findings indicate that chronic fluoxetine impairs the effects of 5-HT1A and 5-HT2C receptors activation in the amygdala and PAG on fear-induced antinociception in mice.
publishDate 2020
dc.date.none.fl_str_mv 2020-12-12T02:38:27Z
2020-12-12T02:38:27Z
2020-03-11
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.3389/fphar.2020.00260
Frontiers in Pharmacology, v. 11.
1663-9812
http://hdl.handle.net/11449/201659
10.3389/fphar.2020.00260
2-s2.0-85082683042
url http://dx.doi.org/10.3389/fphar.2020.00260
http://hdl.handle.net/11449/201659
identifier_str_mv Frontiers in Pharmacology, v. 11.
1663-9812
10.3389/fphar.2020.00260
2-s2.0-85082683042
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Frontiers in Pharmacology
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv Scopus
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
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