Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats

Abstract

Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self-administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders.

Genetic and pharmacological manipulations of glyoxalase 1 mediate ethanol withdrawal seizure susceptibility in mice

“…The finding in Experiment 3 that pBBG treatment only produced a trend toward a significant effect following one cycle of ethanol exposure but led to robust decreases in HIC severity after two cycles, suggests that GLO1 inhibition may be more effective in dependent animals than in non-dependent animals. This is consistent with previous findings where pBBG was more effective at reducing ethanol drinking in dependent rats compared to non-dependent rats (de Guglielmo et al 2018). In the present study there was not a significant ethanol cycle x treatment group interaction (data not shown), so we cannot state conclusively what may be driving the increased efficacy seen with two ethanol withdrawal cycles.…”

“…The GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) was synthesized in the laboratory of Alexander Arnold at the University of Wisconsin Milwaukee, as previously described (McMurray et al, 2017). The dose of 25 mg/kg was chosen because it was believed to be an intermediate dose in the behaviorally-active range; 12.5 mg/kg and 50 mg/kg doses have been shown to reduce ethanol drinking and anxiety-like behavior, respectively in previous studies (McMurray et al 2017, Distler et al 2012, and 25 mg/kg can attenuate withdrawal-associated escalation of ethanol drinking in dependent rats (de Guglielmo et al 2018). pBBG was dissolved in vehicle (8% DMSO/18% tween80/saline) and administered i.p.…”

“…Genetic and pharmacological manipulations of the GLO1 system, as well as direct administration of MG, have been associated with changes in anxiety-and depression-like behaviors, ethanol consumption, and seizure threshold. Specifically, decreased anxiety-like behavior [23,24], decreased depression-like behavior [25,26], decreased ethanol consumption [27,28], and decreased susceptibility to pilocarpine-and picrotoxin-induce seizures [29] have all been seen following GLO1 inhibitor treatment. Some of these effects are also produced by genetic knockdown of Glo1 or direct MG administration.…”

Role of glyoxalase 1 in methylglyoxal detoxification–the broad player of psychiatric disorders

“…Pretreatment with a GLO1 inhibitor also alleviated pilocarpine-induced seizures, whereas Glo1 overexpression exacerbated seizures and decreased the MG concentration in the brain. Likewise, GLO1 inhibitors reduced alcohol consumption [ 82 , 83 ] and handling-induced convulsion after alcohol injection [ 84 ], whereas Glo1 overexpression exacerbated these effects. In addition, alcohol consumption was reduced in Glo1 hemizygous-knockdown mice [ 82 ].…”

A Framework to Analyse and Interpret Mouse Functional Genome by Prioritizing High Impact SNPs

“…In total, mMAP analysis identified 299 rSNPs in Nrxn3, and any of these could alter its splicing. SNPs in Glyoxalase 1 (GLO1) have been associated with the level of alcohol consumption, and it has been considered as a therapeutic target for treatment of alcoholism33 . mMAP identified 34 SNPs located within or enhancer regions in…”