Progesterone modulation of alpha5 nAChR subunits influences anxiety-related behavior during estrus cycle.
Progesterone modulation of alpha5 nAChR subunits influences anxiety-related behavior during estrus cycle.
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DOI：
10.1111/j.1601-183x.2009.00476.x
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发表时间：
2009-06
期刊：
影响因子：
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通讯作者：
De Biasi M
中科院分区：
文献类型：
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作者：
Gangitano D;Salas R;Teng Y;Perez E;De Biasi M
吸烟者经常报告香烟的抗焦虑作用。此外，焦虑、创伤后应激综合症和抑郁症等压力相关疾病通常与长期使用尼古丁有关。为了研究α5烟碱乙酰胆碱受体亚基在焦虑相关反应中的作用，对对照组和α5亚基缺失小鼠（α5 −/−）进行了旷场、光-暗箱和高架十字迷宫试验。在开放视野和明暗箱中，α5 −/−表现得像野生型对照。在升高的阳性组中，雌性α5 −/−小鼠表现出抗焦虑样表型，而雄性α5 −/−小鼠与同窝对照小鼠无法区分。我们通过测定血浆皮质酮和下丘脑促肾上腺皮质激素释放因子来研究下丘脑-垂体-肾上腺轴。与抗焦虑样表型一致，雌性α5 −/−小鼠表现出较低的基础皮质酮水平。为了测试性腺类固醇是否调节α5的表达，我们用孕酮处理培养的NT 2细胞，发现α5蛋白水平上调。此外，脑α5 mRNA水平增加后，孕酮注射到卵巢切除的野生型女性。最后，我们在高架十字迷宫中测试了发情周期中的焦虑水平。在野生型小鼠中，发情期（孕酮水平较低时）具有抗焦虑作用，但在α5 −/−雌性小鼠中未发现焦虑水平的周期依赖性波动。因此，含α5的nAChR可能是焦虑反应的介质，α5表达的甾体酮依赖性调节可能导致卵巢周期中焦虑水平的波动。
Smokers often report an anxiolytic effect of cigarettes. In addition, stress-related disorders such as anxiety, post-traumatic stress syndrome, and depression are often associated with chronic nicotine use. To study the role of the α5 nicotinic acetylcholine receptor subunit in anxiety-related responses, control and α5 subunit null mice (α5 −/−) were subjected to the open field, light-dark box and elevated plus maze tests. In the open field and light-dark box, α5 −/− behaved like wild type controls. In the elevated plus, female α5 −/− mice displayed an anxiolytic-like phenotype while male α5 −/− mice were undistinguishable from littermate controls. We studied the hypothalamus-pituitary-adrenal axis by measuring plasma corticosterone and hypothalamic corticotropin releasing factor. Consistent with an anxiolytic-like phenotype, female α5 −/− mice displayed lower basal corticosterone levels. To test whether gonadal steroids regulate the expression of α5, we treated cultured NT2 cells with progesterone and found that α5 protein levels were up-regulated. In addition, brain levels of α5 mRNA increased upon progesterone injection into ovariectomized wild type females. Finally, we tested anxiety levels in the elevated plus maze during the estrous cycle. The estrus phase (when progesterone levels are low) is anxiolytic-like in wild type mice, but no cycle-dependent fluctuations in anxiety levels were found in α5 −/− females. Thus, α5-containing nAChRs may be mediators of anxiogenic responses, and progesterone-dependent modulation of α5 expression may contribute to fluctuations in anxiety levels during the ovarian cycle.