title: 11β-hydroxysteroid dehydrogenase inhibition as a new potential therapeutic target for alcohol abuse.
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.
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Sanna
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
authors.forename: G F
authors.initials: GF
authors.lastname: Koob
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Roberts
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse-National Institutes of Health, Baltimore, MD, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Vendruscolo
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Repunte-Canonigo
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors*; D000428:Alcohol Drinking; D000437:Alcoholism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D063425:Binge Drinking; D002229:Carbenoxolone / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D002755:Choice Behavior / Q000187:drug effects; D003216:Conditioning, Operant; D004195:Disease Models, Animal; D004327:Drinking Behavior / Q000187:drug effects*; D000431:Ethanol / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D002229:Carbenoxolone