Behavioural Consequences of P‐Glycoprotein Deficiency in Mice, with Special Focus on Stress‐Related Mechanisms
Behavioural Consequences of P‐Glycoprotein Deficiency in Mice, with Special Focus on Stress‐Related Mechanisms
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DOI：
10.1111/j.1365-2826.2012.02278.x
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发表时间：
2012-05
影响因子：
3.2
通讯作者：
Y. Schoenfelder;C. Hiemke;U. Schmitt
中科院分区：
文献类型：
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作者：
Y. Schoenfelder;C. Hiemke;U. Schmitt
P -糖蛋白（P - gp）是一种定位于血脑屏障的外排转运蛋白，可限制多种外源药物进入中枢神经系统。它是否也在内源性糖皮质激素皮质酮的运输中发挥作用是一个有争议的问题。P‐gp敲除小鼠模型[abcb1a/b(−/−)]已被证明在下丘脑-垂体-肾上腺（HPA）轴的功能上存在差异。在本研究中，我们研究了abcb1a/b（−/−）和野生型小鼠在应激相关测试中的行为和皮质酮的影响。在4天的野外（OF）试验、naïve和应激条件下的强迫游泳试验（FST）和悬尾试验（TST）中评估行为活动。外源性皮质酮注射（0.25和2.5 mg/kg）后也进行FST。此外，还评估了升高+迷宫测试和RotaRod测试（RotaRod Advanced; TSE Systems, Bad Homburg, Germany）。脑皮质酮水平采用免疫分析法测定，糖皮质激素受体表达采用western blot分析。Abcb1a/1b（−/−）小鼠脑皮质酮水平显著降低，糖皮质激素受体表达显著升高。行为分析显示，与野生型小鼠相比，abcb1a/1b（−/−）小鼠在前2天的OF测试活性显著降低，尽管习惯化后这种差异消失。在基础和应激条件下，abcb1a/1b（−/−）小鼠FST的不动时间显著减少，而在所有条件下，这些小鼠TST的不动时间均显著增加。注射外源性皮质酮可显著降低abcb1a/1b（−/−）小鼠FST的不动性，而野生型小鼠对相同剂量没有反应。升高+迷宫试验和RotaRod试验无显著性差异。本研究的结果表明，P - gp缺乏对应激相关行为有影响，可能是由于HPA轴反馈调节的差异。
P‐glycoprotein (P‐gp), an efflux transporter localised in the blood–brain barrier, limits the access of multiple xenobiotics to the central nervous system. Whether it is also implemented in the transport of the endogenous glucocorticoid corticosterone is a matter of debate. The P‐gp knockout mouse model [abcb1a/b (−/−)] has been shown to differ in the functioning of the hypothalamic‐pituitary adrenal (HPA) axis. In the present study, we investigated the behaviour of abcb1a/b (−/−) and wild‐type mice with respect to stress‐related tests and the effects of corticosterone. Behavioural activities were assessed in the open field (OF) test for 4 days, and in the forced swimming test (FST) and tail suspension test (TST) under naïve and stressed conditions. The FST was also conducted after exogenous corticosterone injection (0.25 and 2.5 mg/kg). Moreover, the elevated plus maze test and the RotaRod test (RotaRod Advanced; TSE Systems, Bad Homburg, Germany) were assessed. Brain corticosterone levels were determined by an immunoassay and expression of glucocorticoid receptors by western blot analysis. Abcb1a/1b (−/−) mice showed significantly decreased brain corticosterone levels and elevated glucocorticoid receptor expression. Behavioural analysis revealed a significantly decreased activity in the OF test on the first 2 days in abcb1a/1b (−/−) mice compared to wild‐type mice, although the differences disappeared under habituation. Immobility time in the FST was significantly decreased in abcb1a/1b (−/−) mice under basal and under stressed conditions, whereas immobility in the TST was significantly elevated in these mice under all conditions. Injection of exogenous corticosterone resulted in significant reductions of immobility in the FST in abcb1a/1b (−/−) mice, whereas wild‐type mice did not respond to the same doses. There were no differences in the elevated plus maze test and RotaRod test. The results obtained in the present study demonstrate that a P‐gp deficiency has an impact on the stress‐related behaviour, possibly as a result of differences in HPA axis‐feedback regulation.