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Mechanisms involved in the sex-dependent dopaminergic neurodegeneration induced by MDMA in a mouse model of adolescent drug exposure

Year: 2026

Type: article

Abstract: Background 3,4-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. Methods Male 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). Results Male 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). Conclusion MDMA 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.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1964354