title: Genetic and pharmacological manipulation of glyoxalase 1 regulates voluntary ethanol consumption in mice.
abstract: Previous studies have identified an association between the gene glyoxalase 1 (Glo1) and anxiety-like behavior in mice and have shown that the substrate of GLO1, methylglyoxal, is a competitive partial agonist at GABAAreceptors. Given the well-established role of GABAAreceptors in the behavioral effects of ethanol (EtOH), we investigated the role of Glo1 in voluntary EtOH consumption in mice using the drinking in the dark (DID) paradigm. Transgenic mice overexpressing Glo1 on both FVB/NJ (FVB) or C57BL/6J (B6) backgrounds showed increased voluntary EtOH consumption compared to their wild-type littermates in DID. Furthermore, transgenic Glo1 knockdown mice on a B6 background showed decreased voluntary EtOH consumption in DID. These genetic manipulations of Glo1 had no effect on sucrose, saccharin or water consumption. Finally, we found that a small molecule GLO1 inhibitor (S-bromobenzylglutathione cyclopentyl diester (pBBG; 6.25, 12.5 mg/kg)) reduced EtOH consumption compared to vehicle treated B6 mice without altering saccharin or water consumption. Sucrose consumption was only reduced by the higher (12.5 mg/kg) dose of pBBG. We did not observe differences in the loss of righting reflex (LORR) or EtOH-induced foot slips on the balance beam in response to acute EtOH administration (LORR: 4 g/kg, Balance Beam: 1.25 g/kg) in B6 or FVB mice overexpressing Glo1, nor in B6 mice treated with pBBG. These data are the first to implicate Glo1 in EtOH-related behaviors and suggest that GLO1 inhibitors may have therapeutic potential for the treatment of alcohol use disorders.
authors.affiliation: Committee on Neurobiology, University of Chicago, Chicago, IL, 60637, USA.|Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA.
authors.forename: Katherine M J
authors.initials: KM
authors.lastname: McMurray
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee and the Milwaukee Institute for Drug Discovery, Milwaukee, WI, USA.
authors.forename: Preetpal S
authors.initials: PS
authors.lastname: Sidhu
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee and the Milwaukee Institute for Drug Discovery, Milwaukee, WI, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee and the Milwaukee Institute for Drug Discovery, Milwaukee, WI, USA.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA.|Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, 60637, USA.|Department of Psychiatry, University of Californian San Diego, La Jolla, CA, 92093, USA.
authors.forename: Abraham A
authors.initials: AA
authors.lastname: Palmer
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D055785:Gene Knockdown Techniques; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011765:Pyruvaldehyde / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D057897:Reflex, Righting / Q000187:drug effects; D012439:Saccharin / Q000008:administration & dosage; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D014867:Water / Q000008:administration & dosage
chemical_list: D002492:Central Nervous System Depressants; D011963:Receptors, GABA-A; D013549:Sweetening Agents; D014867:Water; D000431:Ethanol; D013395:Sucrose; D011765:Pyruvaldehyde; C000624928:Glo1 protein, mouse; D007791:Lactoylglutathione Lyase; D012439:Saccharin
keywords: Alcohol use disorder; GLO1; drinking in the dark; ethanol consumption; methylglyoxal