Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy.
National Research Council of Italy, Neuroscience Institute, Cagliari, Italy.
Neurotox Res. 2017 Nov;32(4):563-574. doi: 10.1007/s12640-017-9761-6. Epub 2017 Jun 9.
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.
安非他命相关药物 3,4-亚甲二氧基甲基苯丙胺（MDMA）已知会导致小鼠大脑多巴胺能区域的神经毒性损伤。为了描述给药次数如何影响 MDMA 诱导的多巴胺能损伤的严重程度，并描述这种损伤的定位和持续时间，我们评估了不同脑区酪氨酸羟化酶（TH）和多巴胺转运体（DAT）的变化。此外，我们通过评估去甲肾上腺素转运体（NET）、谷氨酸脱羧酶-67（GAD-67）和血清素转运体（SERT）的变化，研究了多巴胺能损伤是否与去甲肾上腺素能、GABA 能和 5-羟色胺能损伤有关。小鼠接受 14、28 或 36 次 MDMA 给药（每周两次，10mg/kg），并在不同时间点（出生后 85、110、138 或 214 天）处死，用于免疫组织化学评估。接受 28 次给药的小鼠在尾壳核（CPu）和内侧前额叶皮质（mPFC）中 DAT 阳性纤维的水平降低，黑质 TH 阳性神经元的水平降低。这些小鼠还显示出海马区 NET 阳性纤维增加，CPu 和海马区 GAD-67 阳性神经元减少，mPFC 区 GAD-67 阳性纤维减少。接受 36 次给药的小鼠也观察到 MDMA 对 DAT、TH 和 GAD-67 的类似影响，并且还显示纹状体、皮质和海马区 TH 免疫反应性纤维水平降低。MDMA 停药 3 个月后，多巴胺能标志物和 GAD-67 的减少仍然存在。最后，MDMA 从未改变 SERT 的水平。这些结果提供了对 MDMA 诱导的多巴胺能损伤的定位和持续时间的进一步深入了解，并表明这种效应可能与 GABA 能有关，而与去甲肾上腺素能或 5-羟色胺能无关。
