Sanna P P, Kawamura T, Chen J, Koob G F, Roberts A J, Vendruscolo L F, Repunte-Canonigo V
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
Transl Psychiatry. 2016 Mar 15;6(3):e760. doi: 10.1038/tp.2016.13.
The identification of new and more effective treatments for alcohol abuse remains a priority. Alcohol intake activates glucocorticoids, which have a key role in alcohol's reinforcing properties. Glucocorticoid effects are modulated in part by the activity of 11β-hydroxysteroid dehydrogenases (11β-HSD) acting as pre-receptors. Here, we tested the effects on alcohol intake of the 11β-HSD inhibitor carbenoxolone (CBX, 18β-glycyrrhetinic acid 3β-O-hemisuccinate), which has been extensively used in the clinic for the treatment of gastritis and peptic ulcer and is active on both 11β-HSD1 and 11β-HSD2 isoforms. We observed that CBX reduces both baseline and excessive drinking in rats and mice. The CBX diastereomer 18α-glycyrrhetinic acid 3β-O-hemisuccinate (αCBX), which we found to be selective for 11β-HSD2, was also effective in reducing alcohol drinking in mice. Thus, 11β-HSD inhibitors may be a promising new class of candidate alcohol abuse medications, and existing 11β-HSD inhibitor drugs may be potentially re-purposed for alcohol abuse treatment.
寻找针对酒精滥用的新型且更有效的治疗方法仍然是一个优先事项。酒精摄入会激活糖皮质激素，而糖皮质激素在酒精的强化特性中起关键作用。糖皮质激素的作用部分受作为前受体的11β-羟基类固醇脱氢酶（11β-HSD）的活性调节。在此，我们测试了11β-HSD抑制剂甘珀酸（CBX，18β-甘草次酸3β-O-半琥珀酸）对酒精摄入的影响，该抑制剂已在临床上广泛用于治疗胃炎和消化性溃疡，并且对11β-HSD1和11β-HSD2两种亚型均有活性。我们观察到CBX可降低大鼠和小鼠的基线饮酒量及过量饮酒量。我们发现对11β-HSD2具有选择性的CBX非对映体18α-甘草次酸3β-O-半琥珀酸（αCBX）在降低小鼠酒精饮用量方面也有效。因此，11β-HSD抑制剂可能是一类有前景的新型酒精滥用治疗候选药物，现有的11β-HSD抑制剂药物可能有用于酒精滥用治疗的潜在用途。
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