11β-hydroxysteroid dehydrogenase inhibition as a new potential therapeutic target for alcohol abuse

Transl Psychiatry. 2016 Mar 15;6(3):e760. doi: 10.1038/tp.2016.13.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors*
  • Alcohol Drinking
  • Alcoholism*
  • Animals
  • Behavior, Animal / drug effects*
  • Binge Drinking
  • Carbenoxolone / pharmacology*
  • Central Nervous System Depressants / administration & dosage*
  • Choice Behavior / drug effects
  • Conditioning, Operant
  • Disease Models, Animal
  • Drinking Behavior / drug effects*
  • Ethanol / administration & dosage*
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Rats, Wistar
  • Self Administration

Substances

  • Central Nervous System Depressants
  • Ethanol
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • Carbenoxolone