Achat-Mendes Cindy, Anderson Karen L, Itzhak Yossef
Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami, FL 33136, USA.
Neuropsychopharmacology. 2007 Mar;32(3):531-41. doi: 10.1038/sj.npp.1301119. Epub 2006 Jun 7.
Some of the major concerns related to methamphetamine (METH) abuse are the neuronal damage inflicted at dopamine (DA) nerve terminals and the cognitive deficits observed in human METH abusers. We have shown that a high dose of METH selectively depleted dopaminergic markers in striatum, frontal cortex and amygdala of Swiss Webster mice, and impaired learned place preference. In this study, we investigated whether deficits in consolidation of place learning, as a consequence of METH neurotoxicity, underlie the underperformance of cocaine conditioned place preference (CPP). Administration of METH (5 mg/kg x 3) to Swiss Webster mice decreased striatal tyrosine hydroxylase (TH) immunoreactive neurons and significantly increased glial fibrillary acidic protein (GFAP) expression, confirming the neurotoxic potential of METH in mice. This treatment significantly attenuated the establishment of cocaine (15 mg/kg) CPP compared to control. To investigate whether manipulation of the consolidation phase improves learned place preference, mice were trained by cocaine and received daily post-training injections of DA receptor agonists or N-acetylcysteine (NAC). As memory consolidation occurs shortly after training, drugs were administered either immediately or 2 h post-training. Immediate post-training administration of the D1 DA receptor agonist SKF38393 (5, 10, and 20 mg/kg) or the D2 DA receptor agonist quinpirole (0.25, 0.5, and 1.0 mg/kg) did not improve the establishment of CPP following METH neurotoxicity. However, immediate but not delayed NAC administration (50 and 100 mg/kg) enhanced cocaine CPP following METH neurotoxicity and had no effect on control CPP. The levels of the reduced form of glutathione (GSH) in striatum, amygdala, hippocampus and frontal cortex were significantly lower in METH-treated mice compared to control during the period of CPP training. Acute and repeated administration of NAC to METH-treated mice restored the decreased brain GSH but had no effect on controls. Results suggest that METH-induced dopaminergic neurotoxicity is associated with impairment of consolidation of learned place preference, and that this impairment is improved by immediate post-training administration of the glutathione precursor NAC and not by D1 or D2 DA receptor agonists. Restoration of brain glutathione levels immediately post-training may facilitate the consolidation process.
与甲基苯丙胺（METH）滥用相关的一些主要问题是多巴胺（DA）神经末梢所遭受的神经元损伤以及在人类甲基苯丙胺滥用者中观察到的认知缺陷。我们已经表明，高剂量的甲基苯丙胺选择性地耗尽了瑞士韦伯斯特小鼠纹状体、额叶皮质和杏仁核中的多巴胺能标记物，并损害了习得性位置偏爱。在本研究中，我们调查了作为甲基苯丙胺神经毒性后果的位置学习巩固缺陷是否是可卡因条件性位置偏爱（CPP）表现不佳的原因。给瑞士韦伯斯特小鼠注射甲基苯丙胺（5mg/kg×3）可减少纹状体酪氨酸羟化酶（TH）免疫反应性神经元，并显著增加胶质纤维酸性蛋白（GFAP）表达，证实了甲基苯丙胺在小鼠中的神经毒性潜力。与对照组相比，这种处理显著减弱了可卡因（15mg/kg）CPP的建立。为了研究操纵巩固阶段是否能改善习得性位置偏爱，小鼠用可卡因进行训练，并在每天训练后注射多巴胺受体激动剂或N-乙酰半胱氨酸（NAC）。由于记忆巩固在训练后不久发生，药物在训练后立即或2小时给药。训练后立即给予D1多巴胺受体激动剂SKF38393（5、10和20mg/kg）或D2多巴胺受体激动剂喹吡罗（0.25、0.5和1.0mg/kg）并不能改善甲基苯丙胺神经毒性后CPP的建立。然而，训练后立即而非延迟给予NAC（50和100mg/kg）可增强甲基苯丙胺神经毒性后的可卡因CPP，且对对照CPP无影响。在CPP训练期间，与对照组相比，甲基苯丙胺处理的小鼠纹状体、杏仁核、海马体和额叶皮质中还原型谷胱甘肽（GSH）水平显著降低。对甲基苯丙胺处理的小鼠急性和重复给予NAC可恢复降低的脑内GSH，但对对照组无影响。结果表明，甲基苯丙胺诱导的多巴胺能神经毒性与习得性位置偏爱巩固受损有关，并且训练后立即给予谷胱甘肽前体NAC可改善这种损伤，而D1或D2多巴胺受体激动剂则不能。训练后立即恢复脑内谷胱甘肽水平可能有助于巩固过程。
