Department of Psychiatry and Psychotherapy, University Medical Centre of the Johannes Gutenberg-University Mainz, Mainz, Germany.
J Neuroendocrinol. 2012 May;24(5):809-17. doi: 10.1111/j.1365-2826.2012.02278.x.
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.
P-糖蛋白（P-gp）是一种位于血脑屏障中的外排转运体，限制了多种外源性物质进入中枢神经系统。它是否也参与了内源性糖皮质激素皮质酮的转运仍存在争议。P-gp 敲除小鼠模型[abcb1a/b（-/-）]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和皮质酮作用方面的行为。在旷场（OF）测试中进行了 4 天的行为活动评估，并在基础和应激条件下进行了强迫游泳测试（FST）和悬尾测试（TST）。在 FST 之后还进行了外源性皮质酮注射（0.25 和 2.5 mg/kg）。此外，还进行了高架十字迷宫测试和转棒测试（RotaRod Advanced；TSE Systems，Bad Homburg，德国）。通过免疫测定法测定脑皮质酮水平，并通过 Western blot 分析测定糖皮质激素受体的表达。abcb1a/1b（-/-）小鼠的脑皮质酮水平显著降低，糖皮质激素受体表达升高。行为分析显示，与野生型小鼠相比，abcb1a/1b（-/-）小鼠在 OF 测试的前 2 天的活动明显减少，尽管在适应后差异消失。在基础和应激条件下，abcb1a/1b（-/-）小鼠的 FST 不动时间显著减少，而在所有条件下，这些小鼠的 TST 不动时间显著增加。外源性皮质酮注射导致 abcb1a/1b（-/-）小鼠的 FST 不动时间显著减少，而野生型小鼠对相同剂量没有反应。在高架十字迷宫测试和转棒测试中没有差异。本研究的结果表明，P-gp 缺乏会对与应激相关的行为产生影响，这可能是由于 HPA 轴反馈调节的差异所致。
