Krasnova Irina N, Hodges Amber B, Ladenheim Bruce, Rhoades Raina, Phillip Crystal G, Cesena Angela, Ivanova Ekaterina, Hohmann Christine F, Cadet Jean Lud
Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse, NIH/DHHS, Baltimore, MD 21224, USA.
Neurosci Res. 2009 Oct;65(2):160-5. doi: 10.1016/j.neures.2009.06.007. Epub 2009 Jun 24.
Methamphetamine (METH) is a psychostimulant that causes damage to dopamine (DA) axons and to non-monoaminergic neurons in the brain. The aim of the present study was to investigate short- and long-term effects of neurotoxic METH treatment on novelty-induced locomotor activity in mice. Male BALB/c mice, 12-14 weeks old, were injected with saline or METH (i.p., 7.5 mg/kg x 4 times, every 2 h). Behavior and neurotoxic effects were assessed at 10 days, 3 and 5 months following drug treatment. METH administration caused marked decreases in DA levels in the mouse striatum and cortex at 10 days post-drug. However, METH did not induce any changes in novelty-induced locomotor activity. At 3 and 5 months after treatment METH-exposed mice showed significant recovery of DA levels in the striatum and cortex. In contrast, these animals demonstrated significant decreases in locomotor activity at 5 months in comparison to aged-matched control mice. Further assessment of METH toxicity using TUNEL staining showed that the drug induced increased cell death in the striatum and cortex at 3 days after administration. Taken together, these data suggest that delayed deficits in novelty-induced locomotor activity observed in METH-exposed animals are not due to neurodegeneration of DA terminals but to combined effects of METH and age-dependent dysfunction of non-DA intrinsic striatal and/or corticostriatal neurons.
甲基苯丙胺（METH）是一种精神兴奋剂，会对大脑中的多巴胺（DA）轴突和非单胺能神经元造成损害。本研究的目的是调查神经毒性甲基苯丙胺治疗对小鼠新奇诱导的运动活动的短期和长期影响。12 - 14周龄的雄性BALB/c小鼠腹腔注射生理盐水或甲基苯丙胺（7.5mg/kg，每2小时一次，共4次）。在药物治疗后的10天、3个月和5个月评估行为和神经毒性作用。给药后10天，甲基苯丙胺导致小鼠纹状体和皮质中的多巴胺水平显著下降。然而，甲基苯丙胺并未引起新奇诱导的运动活动的任何变化。治疗后3个月和5个月，暴露于甲基苯丙胺的小鼠纹状体和皮质中的多巴胺水平显著恢复。相比之下，与年龄匹配的对照小鼠相比，这些动物在5个月时的运动活动显著下降。使用TUNEL染色对甲基苯丙胺毒性进行的进一步评估表明，给药后3天，该药物诱导纹状体和皮质中的细胞死亡增加。综上所述，这些数据表明，在暴露于甲基苯丙胺的动物中观察到的新奇诱导的运动活动的延迟缺陷不是由于多巴胺终末的神经变性，而是由于甲基苯丙胺的综合作用以及非多巴胺固有纹状体和/或皮质纹状体神经元的年龄依赖性功能障碍。
