Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline

Autores
Granado, Noelia; Mendieta, Liliana; Tizabi, Yousef; Murer, Mario Gustavo; Moratalla, Rosario
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Methamphetamine (METH) abuse increases worldwide. In addition to its acute life-threatening effects, METH is toxic for dopaminergic neurons, increasing the risk of developing Parkinson´s disease. The impact of repeated METH binge consumption on dopaminergic and neurotoxicity markers remains unclear. We exposed mice to a repeated “binge-like” METH regime, consisting of three doses over a 6 h interval, repeated three times with 14-day intervals. After the first binge, spontaneous motor activity decreased markedly but remained normal after subsequent binges. Following the first binge, we observed a 25 % loss of nigral dopaminergic cell bodies and significant axon terminal damage as assessed through striatal silver staining, with minimal further degeneration after additional binges. Dopaminergic markers were substantially depleted after the first and second binges, despite partial recovery between binges, dropping to below 20 % of control levels. By one day after the third binge, tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) stabilized at 50–60 % of control levels, but the dopamine transporter (DAT) remained at only 25 %, showing less recovery. These changes were accompanied by an evolving neuroinflammation pattern, with a transient microglial surge after the first binge and persistent astroglial and temperature responses. Overall, our findings indicate partial recovery of dopaminergic markers and the development of tolerance to METH neurotoxicity. The robust reduction of DAT after the first binge may contribute to this tolerance to subsequence binges by limiting METH entry into neurons thereby mitigating its neurotoxic effects.
Fil: Granado, Noelia. Instituto de Salud Carlos III; España. Consejo Superior de Investigaciones Científicas; España
Fil: Mendieta, Liliana. Instituto de Salud Carlos III; España. Consejo Superior de Investigaciones Científicas; España
Fil: Tizabi, Yousef. Howard University College of Medicine; Estados Unidos
Fil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Moratalla, Rosario. Consejo Superior de Investigaciones Científicas; España. Instituto de Salud Carlos III; España
Materia
Parkinson's disease
methamphetamine
neurotoxicity
drug addiction
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:11336/273562
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/273562
network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) declineGranado, NoeliaMendieta, LilianaTizabi, YousefMurer, Mario GustavoMoratalla, RosarioParkinson's diseasemethamphetamineneurotoxicitydrug addictionhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Methamphetamine (METH) abuse increases worldwide. In addition to its acute life-threatening effects, METH is toxic for dopaminergic neurons, increasing the risk of developing Parkinson´s disease. The impact of repeated METH binge consumption on dopaminergic and neurotoxicity markers remains unclear. We exposed mice to a repeated “binge-like” METH regime, consisting of three doses over a 6 h interval, repeated three times with 14-day intervals. After the first binge, spontaneous motor activity decreased markedly but remained normal after subsequent binges. Following the first binge, we observed a 25 % loss of nigral dopaminergic cell bodies and significant axon terminal damage as assessed through striatal silver staining, with minimal further degeneration after additional binges. Dopaminergic markers were substantially depleted after the first and second binges, despite partial recovery between binges, dropping to below 20 % of control levels. By one day after the third binge, tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) stabilized at 50–60 % of control levels, but the dopamine transporter (DAT) remained at only 25 %, showing less recovery. These changes were accompanied by an evolving neuroinflammation pattern, with a transient microglial surge after the first binge and persistent astroglial and temperature responses. Overall, our findings indicate partial recovery of dopaminergic markers and the development of tolerance to METH neurotoxicity. The robust reduction of DAT after the first binge may contribute to this tolerance to subsequence binges by limiting METH entry into neurons thereby mitigating its neurotoxic effects.Fil: Granado, Noelia. Instituto de Salud Carlos III; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Mendieta, Liliana. Instituto de Salud Carlos III; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Tizabi, Yousef. Howard University College of Medicine; Estados UnidosFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Moratalla, Rosario. Consejo Superior de Investigaciones Científicas; España. Instituto de Salud Carlos III; EspañaAcademic Press Inc Elsevier Science2025-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/273562Granado, Noelia; Mendieta, Liliana; Tizabi, Yousef; Murer, Mario Gustavo; Moratalla, Rosario; Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline; Academic Press Inc Elsevier Science; Neurobiology of Disease; 207; 4-2025; 1-130969-9961CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0969996125000555info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2025.106839info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:55:15Zoai:ri.conicet.gov.ar:11336/273562instacron: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:34982025-11-12 09:55:15.704CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline
title Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline
spellingShingle Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline
Granado, Noelia
Parkinson's disease
methamphetamine
neurotoxicity
drug addiction
title_short Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline
title_full Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline
title_fullStr Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline
title_full_unstemmed Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline
title_sort Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline
dc.creator.none.fl_str_mv Granado, Noelia
Mendieta, Liliana
Tizabi, Yousef
Murer, Mario Gustavo
Moratalla, Rosario
author Granado, Noelia
author_facet Granado, Noelia
Mendieta, Liliana
Tizabi, Yousef
Murer, Mario Gustavo
Moratalla, Rosario
author_role author
author2 Mendieta, Liliana
Tizabi, Yousef
Murer, Mario Gustavo
Moratalla, Rosario
author2_role author
author
author
author
dc.subject.none.fl_str_mv Parkinson's disease
methamphetamine
neurotoxicity
drug addiction
topic Parkinson's disease
methamphetamine
neurotoxicity
drug addiction
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Methamphetamine (METH) abuse increases worldwide. In addition to its acute life-threatening effects, METH is toxic for dopaminergic neurons, increasing the risk of developing Parkinson´s disease. The impact of repeated METH binge consumption on dopaminergic and neurotoxicity markers remains unclear. We exposed mice to a repeated “binge-like” METH regime, consisting of three doses over a 6 h interval, repeated three times with 14-day intervals. After the first binge, spontaneous motor activity decreased markedly but remained normal after subsequent binges. Following the first binge, we observed a 25 % loss of nigral dopaminergic cell bodies and significant axon terminal damage as assessed through striatal silver staining, with minimal further degeneration after additional binges. Dopaminergic markers were substantially depleted after the first and second binges, despite partial recovery between binges, dropping to below 20 % of control levels. By one day after the third binge, tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) stabilized at 50–60 % of control levels, but the dopamine transporter (DAT) remained at only 25 %, showing less recovery. These changes were accompanied by an evolving neuroinflammation pattern, with a transient microglial surge after the first binge and persistent astroglial and temperature responses. Overall, our findings indicate partial recovery of dopaminergic markers and the development of tolerance to METH neurotoxicity. The robust reduction of DAT after the first binge may contribute to this tolerance to subsequence binges by limiting METH entry into neurons thereby mitigating its neurotoxic effects.
Fil: Granado, Noelia. Instituto de Salud Carlos III; España. Consejo Superior de Investigaciones Científicas; España
Fil: Mendieta, Liliana. Instituto de Salud Carlos III; España. Consejo Superior de Investigaciones Científicas; España
Fil: Tizabi, Yousef. Howard University College of Medicine; Estados Unidos
Fil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Moratalla, Rosario. Consejo Superior de Investigaciones Científicas; España. Instituto de Salud Carlos III; España
description Methamphetamine (METH) abuse increases worldwide. In addition to its acute life-threatening effects, METH is toxic for dopaminergic neurons, increasing the risk of developing Parkinson´s disease. The impact of repeated METH binge consumption on dopaminergic and neurotoxicity markers remains unclear. We exposed mice to a repeated “binge-like” METH regime, consisting of three doses over a 6 h interval, repeated three times with 14-day intervals. After the first binge, spontaneous motor activity decreased markedly but remained normal after subsequent binges. Following the first binge, we observed a 25 % loss of nigral dopaminergic cell bodies and significant axon terminal damage as assessed through striatal silver staining, with minimal further degeneration after additional binges. Dopaminergic markers were substantially depleted after the first and second binges, despite partial recovery between binges, dropping to below 20 % of control levels. By one day after the third binge, tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) stabilized at 50–60 % of control levels, but the dopamine transporter (DAT) remained at only 25 %, showing less recovery. These changes were accompanied by an evolving neuroinflammation pattern, with a transient microglial surge after the first binge and persistent astroglial and temperature responses. Overall, our findings indicate partial recovery of dopaminergic markers and the development of tolerance to METH neurotoxicity. The robust reduction of DAT after the first binge may contribute to this tolerance to subsequence binges by limiting METH entry into neurons thereby mitigating its neurotoxic effects.
publishDate 2025
dc.date.none.fl_str_mv 2025-04
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/11336/273562
Granado, Noelia; Mendieta, Liliana; Tizabi, Yousef; Murer, Mario Gustavo; Moratalla, Rosario; Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline; Academic Press Inc Elsevier Science; Neurobiology of Disease; 207; 4-2025; 1-13
0969-9961
CONICET Digital
CONICET
url http://hdl.handle.net/11336/273562
identifier_str_mv Granado, Noelia; Mendieta, Liliana; Tizabi, Yousef; Murer, Mario Gustavo; Moratalla, Rosario; Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline; Academic Press Inc Elsevier Science; Neurobiology of Disease; 207; 4-2025; 1-13
0969-9961
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0969996125000555
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2025.106839
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
dc.publisher.none.fl_str_mv Academic Press Inc Elsevier Science
publisher.none.fl_str_mv Academic Press Inc Elsevier Science
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 12.976206

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