Simões Patrícia F, Silva Ana P, Pereira Frederico C, Marques Elsa, Milhazes Nuno, Borges Fernanda, Ribeiro Carlos F, Macedo Tice R
Biomedical Institute for Research in Light and Image, Azinhaga de Santa Comba, Coimbra, Portugal.
Ann N Y Acad Sci. 2008 Oct;1139:232-41. doi: 10.1196/annals.1432.028.
Methamphetamine (METH) is a powerful psychostimulant whose noxious effects depend largely on the pattern of abuse. METH-induced glutamate release may overactivate N-methyl-d-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (NMDAR and AMPAR, respectively) causing excitotoxicity. In the brain, these receptors are also known for their essential role in mediating memory consolidation. Therefore, we assessed glial fibrillary acidic protein (GFAP) expression as a marker for astrogliosis and neurodegeneration by using Fluoro-Jade C (F-J C) staining. Moreover, we investigated the effect of two METH regimens on NMDAR NR1 and NR2A and on AMPAR GluR2 subunit expression in the rat striatum and frontal cortex 24 h after drug treatment. Adult Sprague-Dawley rats were injected subcutaneously (s.c.) on six consecutive days with saline (control and acute groups) or with an increasing dose of METH (10, 15, 15, 20, 20, 25 mg/kg/day; ED group). On the seventh day, both METH groups were given a "bolus" of 30 mg/kg METH, whereas controls received saline. We evaluated the expression levels of GFAP by both Western blot and immunohistochemical assays and concluded that there was no difference from control levels. In addition, neither drug regimen resulted in neurodegeneration within 24 h of last METH administration. In the frontal cortex of the acute group, NR1 expression level was decreased, and both NR2A and GluR2 were increased. Also, in the striatum of the acute group, the expression level of GluR2 was significantly increased, and both GluR2 and NR2A levels were augmented in the striatum of the ED group. Taken together, these results suggest a protective mechanism by decreasing permeability and/or functionality of AMPAR and NMDAR to counteract METH-induced glutamate overflow in the brain. Moreover, these results may explain, in part, the mnemonic deficits and psychotic behavior associated with METH abuse.
甲基苯丙胺（METH）是一种强效精神兴奋剂，其有害影响在很大程度上取决于滥用模式。METH诱导的谷氨酸释放可能会过度激活N-甲基-D-天冬氨酸和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（分别为NMDAR和AMPAR），从而导致兴奋性毒性。在大脑中，这些受体还因其在介导记忆巩固中的重要作用而闻名。因此，我们通过使用Fluoro-Jade C（F-J C）染色来评估胶质纤维酸性蛋白（GFAP）的表达，作为星形胶质细胞增生和神经退行性变的标志物。此外，我们研究了两种METH给药方案对大鼠纹状体和额叶皮质中NMDAR NR1和NR2A以及AMPAR GluR2亚基表达的影响，给药后24小时进行检测。成年Sprague-Dawley大鼠连续六天皮下注射（s.c.）生理盐水（对照组和急性组）或递增剂量的METH（10、15、15、20、20、25mg/kg/天；ED组）。在第七天，两个METH组均给予30mg/kg的METH“推注”，而对照组给予生理盐水。我们通过蛋白质印迹法和免疫组织化学分析评估了GFAP的表达水平，得出其与对照水平无差异的结论。此外，在最后一次给予METH后的24小时内，两种给药方案均未导致神经退行性变。在急性组的额叶皮质中，NR1表达水平降低，NR2A和GluR2均升高。此外，在急性组的纹状体中，GluR2的表达水平显著升高，在ED组的纹状体中，GluR2和NR2A水平均升高。综上所述，这些结果表明存在一种保护机制，即通过降低AMPAR和NMDAR的通透性和/或功能，以抵消METH诱导的大脑中谷氨酸溢出。此外，这些结果可能部分解释了与METH滥用相关的记忆缺陷和精神行为。
