Progression and Persistence of Neurotoxicity Induced by MDMA in Dopaminergic Regions of the Mouse Brain and Association with Noradrenergic, GABAergic, and Serotonergic Damage

The amphetamine-related drug 3,4-methylenedioxymethamphetamine (MDMA) is known to induce neurotoxic damage in dopaminergic regions of the mouse brain. In order to characterize how the number of administrations influenced the severity of MDMA-induced dopaminergic damage and to describe the localization and persistence of this damage, we evaluated the changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) in different regions of the mouse brain. Moreover, we investigated whether dopaminergic damage was associated with noradrenergic, GABAergic, and serotonergic damage, by evaluating the changes in noradrenaline transporter (NET), glutamic acid decarboxylase-67 (GAD-67), and serotonin transporter (SERT). Mice received 14, 28, or 36 MDMA administrations (10 mg/kg twice a week) and were sacrificed at different time points (postnatal days 85, 110, 138, or 214) for immunohistochemical evaluation. Mice receiving 28 administrations showed reduced levels of DAT-positive fibers in caudate-putamen (CPu) and medial prefrontal cortex (mPFC) and reduced levels of TH-positive nigral neurons. These mice also displayed increased NET-positive hippocampal fibers, reduced GAD-67-positive neurons in CPu and hippocampus, and reduced GAD-67-positive fibers in mPFC. Similar effects of MDMA on DAT, TH, and GAD-67 were found in mice receiving 36 administrations, which also displayed reduced levels of striatal, cortical, and hippocampal TH-immunoreactive fibers. The reductions in dopaminergic markers and GAD-67 persisted at 3 months after MDMA discontinuation. Finally, MDMA never modified the levels of SERT. These results provide further insight into the localization and persistence of MDMA-induced dopaminergic damage and show that this effect may associate with GABAergic but not noradrenergic or serotonergic damage.