Effect of crowding, temperature and age on glia activation and dopaminergic neurotoxicity induced by MDMA in the mouse brain

• MDMA induces glia activation and dopaminergic neurotoxicity in the mouse brain.
• The administration setting influences these effects of MDMA.
• Exposure to crowded environments amplifies MDMA effects on glia and neurotoxicity.
• Exposure to a high environmental temperature amplifies MDMA effects on glia only.
• This study is relevant to human MDMA use, often featuring crowded/hot environments.

3,4-methylenedyoxymethamphetamine (MDMA or “ecstasy”), a recreational drug of abuse, can induce glia activation and dopaminergic neurotoxicity. Since MDMA is often consumed in crowded environments featuring high temperatures, we studied how these factors influenced glia activation and dopaminergic neurotoxicity induced by MDMA. C57BL/6J adolescent (4 weeks old) and adult (12 weeks old) mice received MDMA (4 × 20 mg/kg) in different conditions: 1) while kept 1, 5, or 10 × cage at room temperature (21 °C); 2) while kept 5 × cage at either room (21 °C) or high (27 °C) temperature. After the last MDMA administration, immunohistochemistry was performed in the caudate-putamen for CD11b and GFAP, to mark microglia and astroglia, and in the substantia nigra pars compacta for tyrosine hydroxylase, to mark dopaminergic neurons. MDMA induced glia activation and dopaminergic neurotoxicity, compared with vehicle administration. Crowding (5 or 10 mice × cage) amplified MDMA-induced glia activation (in adult and adolescent mice) and dopaminergic neurotoxicity (in adolescent mice). Conversely, exposure to a high environmental temperature (27 °C) potentiated MDMA-induced glia activation in adult and adolescent mice kept 5 × cage, but not dopaminergic neurotoxicity. Crowding and exposure to a high environmental temperature amplified MDMA-induced hyperthermia, and a positive correlation between body temperature and activation of either microglia or astroglia was found in adult and adolescent mice. These results provide further evidence that the administration setting influences the noxious effects of MDMA in the mouse brain. However, while crowding amplifies both glia activation and dopaminergic neurotoxicity, a high environmental temperature exacerbates glia activation only.

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