Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Subunit 1 - Polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.
Neurotox Res. 2014 Apr;25(3):295-304. doi: 10.1007/s12640-013-9423-2. Epub 2013 Sep 26.
Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis.
甲基苯丙胺（METH）会引发单胺能系统的紊乱，而 METH 滥用会导致戒断期间出现负面情绪状态，包括抑郁症状。然而，目前尚不清楚 METH 的急性毒性剂量是否也会导致持久的抑郁表型和持续的单胺能缺陷。因此，我们现在评估了单次高剂量 METH（30mg/kg，ip）给药后早期和长期对小鼠的抑郁样行为。METH 并未改变游泳速度和在提示版水迷宫任务中寻找平台的逃避潜伏期来评估的小鼠的运动功能和程序性记忆。然而，METH 在给药后 3 天和 49 天显著增加了尾部悬挂测试中的不动时间。METH 诱导的这种抑郁样表型伴随着额纹状体多巴胺能和 5-羟色胺能神经传递的明显耗竭，这表现为多巴胺、DOPAC 和 HVA、酪氨酸羟化酶和 5-羟色胺水平在给药后 3 天和 49 天都降低。平行地，另一种抑郁的神经化学特征——星形胶质细胞功能障碍——在皮质和纹状体水平的星形胶质细胞蛋白标志物胶质纤维酸性蛋白水平没有受到影响，仅在 3 天短暂增加。这些发现首次表明，单次高剂量 METH 会导致小鼠产生持久的抑郁样行为，与额纹状体多巴胺能和 5-羟色胺能平衡的持续破坏有关。
