乙醇对小鼠、大鼠、食蟹猴和人血清 GABA 能 3α,5α/3α,5β 神经活性甾体的差异作用。
Differential effects of ethanol on serum GABAergic 3alpha,5alpha/3alpha,5beta neuroactive steroids in mice, rats, cynomolgus monkeys, and humans.
机构信息
Department of Psychiatry and Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7178, USA.
出版信息
Alcohol Clin Exp Res. 2010 Mar 1;34(3):432-42. doi: 10.1111/j.1530-0277.2009.01123.x. Epub 2009 Dec 17.
BACKGROUND
Acute ethanol administration increases plasma and brain levels of progesterone and deoxycorticosterone-derived neuroactive steroids (3alpha,5alpha)-3-hydroxypregnan-20-one (3alpha,5alpha-THP) and (3alpha,5alpha)-3,21-dihydroxypregnan-20-one (3alpha,5alpha-THDOC) in rats. However, little is known about ethanol effects on GABAergic neuroactive steroids in mice, nonhuman primates, or humans. We investigated the effects of ethanol on plasma levels of 3alpha,5alpha- and 3alpha,5beta-reduced GABAergic neuroactive steroids derived from progesterone, deoxycorticosterone, dehydroepiandrosterone, and testosterone using gas chromatography-mass spectrometry.
METHODS
Serum levels of GABAergic neuroactive steroids and pregnenolone were measured in male rats, C57BL/6J and DBA/2J mice, cynomolgus monkeys, and humans following ethanol administration. Rats and mice were injected with ethanol (0.8 to 2.0 g/kg), cynomolgus monkeys received ethanol (1.5 g/kg) intragastrically, and healthy men consumed a beverage containing 0.8 g/kg ethanol. Steroids were measured after 60 minutes in all species and also after 120 minutes in monkeys and humans.
RESULTS
Ethanol administration to rats increased levels of 3alpha,5alpha-THP, 3alpha,5alpha-THDOC, and pregnenolone at the doses of 1.5 g/kg (+228, +134, and +860%, respectively, p < 0.001) and 2.0 g/kg (+399, +174, and +1125%, respectively, p < 0.001), but not at the dose of 0.8 g/kg. Ethanol did not alter levels of the other neuroactive steroids. In contrast, C57BL/6J mice exhibited a 27% decrease in serum 3alpha,5alpha-THP levels (p < 0.01), while DBA/2J mice showed no significant effect of ethanol, although both mouse strains exhibited substantial increases in precursor steroids. Ethanol did not alter any of the neuroactive steroids in cynomolgus monkeys at doses comparable to those studied in rats. Finally, no effect of ethanol (0.8 g/kg) was observed in men.
CONCLUSIONS
These studies show clear species differences among rats, mice, and cynomolgus monkeys in the effects of ethanol administration on circulating neuroactive steroids. Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses.
背景
急性乙醇摄入会增加大鼠血浆和大脑中孕酮和脱氧皮质酮衍生的神经活性类固醇（3α，5α）-3-羟孕烷-20-酮（3α，5α-THP）和（3α，5α）-3、21-二羟孕烷-20-酮（3α，5α-THDOC）的水平。然而，人们对乙醇对非人类灵长类动物和人类中小鼠 GABA 能神经活性类固醇的影响知之甚少。我们使用气相色谱-质谱法研究了乙醇对来源于孕酮、脱氧皮质酮、脱氢表雄酮和睾酮的 3α，5α-和 3α，5β-还原 GABA 能神经活性类固醇的血浆水平的影响。
方法
在雄性大鼠、C57BL/6J 和 DBA/2J 小鼠、食蟹猴和健康男性中，在给予乙醇后测量 GABA 能神经活性类固醇和孕烯醇酮的血清水平。大鼠和小鼠给予乙醇（0.8 至 2.0 g/kg），食蟹猴给予乙醇（1.5 g/kg）灌胃，健康男性饮用含 0.8 g/kg 乙醇的饮料。在所有物种中，在 60 分钟后测量类固醇，在猴子和人类中也在 120 分钟后测量类固醇。
结果
在 1.5 g/kg（分别增加 228%、134%和 860%，p <0.001）和 2.0 g/kg（分别增加 399%、174%和 1125%，p <0.001）剂量下，乙醇给药增加了 3α，5α-THP、3α，5α-THDOC 和孕烯醇酮的水平，但在 0.8 g/kg 剂量下没有增加。乙醇没有改变其他神经活性类固醇的水平。相比之下，C57BL/6J 小鼠的血清 3α，5α-THP 水平降低了 27%（p <0.01），而 DBA/2J 小鼠的乙醇无明显作用，尽管两种小鼠品系的前体类固醇均显著增加。在与大鼠研究中相当的剂量下，乙醇在食蟹猴中没有改变任何神经活性类固醇。最后，在男性中没有观察到乙醇（0.8 g/kg）的作用。
结论
这些研究表明，在大鼠、小鼠和食蟹猴中，乙醇给药对循环神经活性类固醇的影响存在明显的种间差异。大鼠是唯一具有明显升高 GABA 能神经活性类固醇的物种，而在相当剂量的乙醇下，这种作用在小鼠或食蟹猴中未观察到。
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