Glyoxalase (GLO1) inhibition or genetic overexpression does not alter ethanol’s locomotor effects: implications for GLO1 as a therapeutic target in alcohol use disorders

Abstract

Background: Glyoxalase 1 (GLO1) is an enzyme that metabolizes the glycolytic byproduct methylglyoxal (MG), which is a competitive partial agonist at GABAA receptors.Pharmacological inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol drinking. The present study assessed whether pharmacological inhibition of GLO1, or genetic over expression of Glo1, would also alter the locomotor effects of ethanol, which might explain reduced ethanol consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control.Methods: Male C57BL/6J mice were pretreated with a single dose of either the GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG; 7.5 mg/kg; Experiment 1) or muscimol (0.75 mg/kg; Experiment 2), or their corresponding vehicle. We then determined whether the locomotor response to a range of ethanol doses (0, 0.5, 1.0, 1.5, 2.0, and 2.5) was altered by either pBBG or muscimol pretreatment. We also examined the locomotor response to a range of ethanol doses in FVB/NJ wild type and transgenic Glo1 over expressing mice (Experiment 3).We also assessed anxiety-like behavior as measured by time spent in the center of an open field in all three experiments. Results:The ethanol dose-response curve was not altered by pretreatment with pBBG or by transgenic overexpression of Glo1. In contrast, muscimol blunted locomotor stimulation at low ethanol doses, and potentiated locomotor sedation at higher ethanol doses. Conclusions:The dose of pBBG used in this study has been previously shown to reduce ethanol drinking. Glo1 overexpression has been previously shown to increase ethanol drinking.However, neither manipulation altered the dose response curve for ethanol's locomotor effects, whereas muscimol appeared to enhance the locomotor sedative effects of ethanol. The present ! 2 data demonstrate that reduced ethanol drinking caused by GLO1 inhibition is not due to potentiation of ethanol's stimulant or depressant effects.

A mutant allele of glycoprotein M6‐B (Gpm6b) facilitates behavioral flexibility but increases delay discounting

“…The OF test was administered to measure locomotor activity, as previously described 22–25 . Mice were moved into the testing room and allowed to acclimate for at least 30 min prior to testing.…”

“…The OF test was administered to measure locomotor activity, as previously described. [22][23][24][25] Mice were moved into the testing room and allowed to acclimate for at least 30 min prior to testing. Testing took place between 10:00 and 12:00 h. Mice were placed in the center of a square chamber (43 Â 43 Â 33 cm; the size of the center was 26 Â 16 cm), with dim overhead lighting inside of sound-and lightattenuating boxes, and allowed to freely explore for 30 min.…”

CADM2is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice

“…The third cohort (WT=22; HET=44, HOM=12) was used to measure general locomotion, anxiety-like behavior, and ethanol consumption. Precisely, we assessed general locomotion via the Open Field (50)(51)(52)(53), and anxiety-like behavior via the elevated plus maze [EPM (54)] and light-dark box [LDB (55)]. Lastly, we measured acute voluntary ethanol consumption using a drinking-inthe-dark paradigm [DID, (56)].…”