Enhanced neurodegeneration after a high dose of methamphetamine in adenosine A3 receptor null mutant mice.
Enhanced neurodegeneration after a high dose of methamphetamine in adenosine A3 receptor null mutant mice.
复制标题
DOI：
10.1016/j.neuroscience.2011.08.013
复制
发表时间：
2011-10-27
期刊：
影响因子：
3.3
通讯作者：
Wang, Y.
中科院分区：
文献类型：
--
作者：
Shen, H.;Luo, Y.;Yu, S. -J.;Wang, Y.
已有研究表明腺苷A3受体（A3 R）基因敲除小鼠对缺血性或缺氧性脑损伤更敏感。本研究的目的是检查A3 R表达的抑制是否与高剂量甲基苯丙胺（Methh）诱导的损伤敏感性增加相关。成年雄性A3 R无效突变（-/-）小鼠及其对照（+/+）注射4次剂量（间隔2小时）的Meth（10 mg/kg）或生理盐水。从注射后第一天开始，将动物置于配备有食物和水的行为活动室中52小时。前4小时用于研究探索行为，接下来的48小时用于测量自发活动。高剂量的甲基同样减少了−/−和+/+小鼠的4小时探索行为。在两组中，甲基苯丙胺在4到52小时之间抑制了运动活动，在−/−小鼠中发现了更大的减少。在Meth或盐水注射后3天收集脑组织。通过HPLC检测，甲基苯丙胺治疗降低了+/+和−/−小鼠的纹状体多巴胺（DA）水平，仅在−/−动物中发现DOPAC/DA比率增加。与+/+小鼠相比，甲基苯丙胺还显著增加了纹状体中离子化钙结合接头分子1（Iba-1）和切割的caspase-3水平，以及−/−小鼠黑质中Iba-1和TNFα mRNA的表达。先前的研究表明，利血平对VMAT 2的药理学抑制通过增加胞质DA和炎症增强了Meths毒性。与+/+小鼠相比，在−/−小鼠中发现纹状体VMAT 2表达显著减少，这表明−/−小鼠对甲基损伤的敏感性增加可能与这些小鼠中VMAT 2表达的减少有关。总之，我们的数据表明，A3 R −/−小鼠对高剂量的甲基更敏感。
Previous reports have indicated that adenosine A3 receptor (A3R) knockout mice are more sensitive to ischemic or hypoxic brain injury. The purpose of this study was to examine if suppression of A3R expression is associated with increase in sensitivity to injury induced by a high dose of methamphetamine (Meth). Adult male A3R null mutant (−/−) mice and their controls (+/+) were injected with 4 doses (2 hours apart) of Meth (10 mg/kg) or saline. Animals were placed in a behavioral activity chamber, equipped with food and water, for 52 hours starting from one day after injections. The first 4 hours were used for studying exploratory behaviors and the next 48 hours were used to measure locomotor activity. High doses of Meth equally reduced the 4-hour exploratory behavior in −/− and +/+ mice. Meth suppressed locomotor activity between 4 and 52 hours in both groups, with a greater reduction being found in the −/− mice. Brain tissues were collected at 3 days after the Meth or saline injections. Meth treatment reduced striatal dopamine (DA) levels in both +/+ and −/− mice, examined by HPLC, with an increase in DOPAC/DA ratio being found only in −/− animals. Meth also significantly increased ionized calcium-binding adaptor molecule 1 (Iba-1) and cleaved caspase-3 level in striatum as well as Iba-1 and TNFα mRNA expression in nigra in −/−, compared to +/+, mice. Previous studies have shown that pharmacological suppression of VMAT2 by reserpine enhanced Meth toxicity by increasing cytosolic DA and inflammation. A significant reduction in striatal VMAT2 expression was found in −/− mice, compared to +/+ mice, suggesting that increase in sensitivity to Meth injury in −/− mice may be related to a reduction in VMAT2 expression in these mice. In conclusion, our data suggest that A3R −/− mice are more sensitive to high doses of Meth.
登录
查看更多内容
影响因子：
4.7
作者：
Hammarberg, C;Schulte, G;Fredholm, BB
通讯作者：
Fredholm, BB
影响因子：
4.7
作者：
Brand, A;Vissiennon, Z;Nieber, K
通讯作者：
Nieber, K
影响因子：
2.9
作者：
Guillot, T. S.;Richardson, J. R.;Miller, G. W.
通讯作者：
Miller, G. W.
影响因子：
3.3
作者：
Chou, J.;Luo, Y.;Wang, Y.
通讯作者：
Wang, Y.
影响因子：
3.4
作者：
Mar, A;Spreekmeester, E;Rochford, J
通讯作者：
Rochford, J