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Glyoxalase 1 (GLO1) Inhibition or Genetic Overexpression Does Not Alter Ethanol's Locomotor Effects: Implications for GLO 1 as a Therapeutic Target in Alcohol Use Disorders
Author(s) -
BarkleyLevenson Amanda M.,
Lagarda Frances A.,
Palmer Abraham A.
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13623
Subject(s) - muscimol , agonist , chemistry , gabaa receptor , pharmacology , partial agonist , lactoylglutathione lyase , open field , methylglyoxal , ethanol , locomotor activity , stimulation , receptor , endocrinology , medicine , biochemistry , enzyme
Background Glyoxalase 1 ( GLO 1) is an enzyme that metabolizes methylglyoxal ( MG ), which is a competitive partial agonist at GABA A receptors. Inhibition of GLO 1 increases concentrations of MG in the brain and decreases binge‐like ethanol (EtOH) drinking. This study assessed whether inhibition of GLO 1, or genetic overexpression of Glo1 , would also alter the locomotor effects of EtOH, which might explain reduced EtOH consumption following GLO 1 inhibition. We used the prototypical GABA A receptor agonist muscimol as a positive control. Methods Male C57BL/6J mice were pretreated with either the GLO 1 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 locomotor response to a range of EtOH 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 EtOH doses in FVB / NJ wild‐type and transgenic Glo1 overexpressing mice (Experiment 3). Anxiety‐like behavior (time spent in the center of the open field) was assessed in all 3 experiments. Results The EtOH dose–response curve was not altered by pretreatment with pBBG or by transgenic overexpression of Glo1 . In contrast, muscimol blunted locomotor stimulation at low EtOH doses and potentiated locomotor sedation at higher EtOH doses. No drug or genotype differences were seen in anxiety‐like behavior after EtOH treatment. Conclusions The dose of pBBG used in this study is within the effective range shown previously to reduce EtOH drinking. Glo1 overexpression has been previously shown to increase EtOH drinking. However, neither manipulation altered the dose–response curve for EtOH's locomotor effects, whereas muscimol appeared to enhance the locomotor sedative effects of EtOH. The present data demonstrate that reduced EtOH drinking caused by GLO 1 inhibition is not due to potentiation of EtOH's stimulant or depressant effects.