Mechanisms involved in the sex-dependent dopaminergic neurodegeneration induced by MDMA in a mouse model of adolescent drug exposure
Abstract
Background3,4-Methylenedioxymethamphetamine (MDMA, or “ecstasy”) is an amphetamine-related drug mainly used by adolescents. Studies in mice have demonstrated that MDMA administration induces toxic effects in the nigrostriatal dopaminergic system, some of which may be sex- and age-dependent. Since adolescence is a critical period for brain development, this study aimed to investigate some of the mechanisms underlying MDMA-induced toxicity in the nigrostriatal dopaminergic system of adolescent mice.MethodsMale and female adolescent mice were treated with a regimen of MDMA (4 × 20 mg/kg, 2 h apart) that has previously been demonstrated to induce toxic effects in the nigrostriatal dopaminergic system. After treatment, mice were sacrificed at different time points (i.e., 30, 60 or 120 min) to evaluate loss of nigral dopaminergic neurons, antioxidant and proteasome activity, reactive radical species (RRS) and neurodegeneration-related proteins. Immunohistochemistry for tyrosine hydroxylase (TH) was performed in the substantia nigra pars compacta (SNc). Moreover, midbrains were evaluated for: i) activity of the antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) 1 and 2 of the proteolytic subunits β2 trypsin-like and β5 chymotrypsin-like of the proteasome system; ii) expression of SOD1 and SOD2 genes; iii) presence of RRS and iv) phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and of the signal transducer and activator of transcription 3 (STAT3).ResultsMale mice displayed: i) decreased TH immunoreactivity and cresyl violet staining (120 min after the last MDMA administration); ii) reduced activity of SOD and β2 trypsin-like proteasome subunit, both in basal conditions and 120 min after the last MDMA administration; iii) increase in p-ERK1/2 (30 min after the last MDMA administration). Female mice treated with MDMA displayed: i) decreased SOD1 and SOD2 gene expression and ii) increased GPx activity (both observed 120 min after the last MDMA administration).ConclusionMDMA treatment during adolescence altered the homeostasis of the nigrostriatal dopaminergic system in both male and female mice. Adolescent male mice treated with MDMA appeared more sensitive to dysfunction in proteasome and ERK1/2 activation. Conversely, female mice efficiently maintained the antioxidant activity, which could contrast the neurotoxic effects of MDMA on the nigrostriatal dopaminergic system.
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BibTeX
@article{costa2026mechanisms,
title = {{Mechanisms involved in the sex-dependent dopaminergic neurodegeneration induced by MDMA in a mouse model of adolescent drug exposure}},
author = {Giulia Costa and Laura Rullo and Vera Piera Leoni and Marcello Serra and Camilla Morosini and Fabio Vivarelli and Paola Franchi and Marco Lucarini and Laura Serrau and Fabrizio Sanna and Micaela Morelli and Luigi Atzori and Sanzio Candeletti and Patrizia Romualdi and Nicola Simola},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1964354},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1964354},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mechanisms involved in the sex-dependent dopaminergic neurodegeneration induced by MDMA in a mouse model of adolescent drug exposure
AU - Giulia Costa
AU - Laura Rullo
AU - Vera Piera Leoni
AU - Marcello Serra
AU - Camilla Morosini
AU - Fabio Vivarelli
AU - Paola Franchi
AU - Marco Lucarini
AU - Laura Serrau
AU - Fabrizio Sanna
AU - Micaela Morelli
AU - Luigi Atzori
AU - Sanzio Candeletti
AU - Patrizia Romualdi
AU - Nicola Simola
PY - 2026
DA - 2026/11/06
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1964354
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1964354
AB - Background3,4-Methylenedioxymethamphetamine (MDMA, or “ecstasy”) is an amphetamine-related drug mainly used by adolescents. Studies in mice have demonstrated that MDMA administration induces toxic effects in the nigrostriatal dopaminergic system, some of which may be sex- and age-dependent. Since adolescence is a critical period for brain development, this study aimed to investigate some of the mechanisms underlying MDMA-induced toxicity in the nigrostriatal dopaminergic system of adolescent mice.MethodsMale and female adolescent mice were treated with a regimen of MDMA (4 × 20 mg/kg, 2 h apart) that has previously been demonstrated to induce toxic effects in the nigrostriatal dopaminergic system. After treatment, mice were sacrificed at different time points (i.e., 30, 60 or 120 min) to evaluate loss of nigral dopaminergic neurons, antioxidant and proteasome activity, reactive radical species (RRS) and neurodegeneration-related proteins. Immunohistochemistry for tyrosine hydroxylase (TH) was performed in the substantia nigra pars compacta (SNc). Moreover, midbrains were evaluated for: i) activity of the antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) 1 and 2 of the proteolytic subunits β2 trypsin-like and β5 chymotrypsin-like of the proteasome system; ii) expression of SOD1 and SOD2 genes; iii) presence of RRS and iv) phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and of the signal transducer and activator of transcription 3 (STAT3).ResultsMale mice displayed: i) decreased TH immunoreactivity and cresyl violet staining (120 min after the last MDMA administration); ii) reduced activity of SOD and β2 trypsin-like proteasome subunit, both in basal conditions and 120 min after the last MDMA administration; iii) increase in p-ERK1/2 (30 min after the last MDMA administration). Female mice treated with MDMA displayed: i) decreased SOD1 and SOD2 gene expression and ii) increased GPx activity (both observed 120 min after the last MDMA administration).ConclusionMDMA treatment during adolescence altered the homeostasis of the nigrostriatal dopaminergic system in both male and female mice. Adolescent male mice treated with MDMA appeared more sensitive to dysfunction in proteasome and ERK1/2 activation. Conversely, female mice efficiently maintained the antioxidant activity, which could contrast the neurotoxic effects of MDMA on the nigrostriatal dopaminergic system.
SN - 1663-9812
ER -