Department of Psychiatry, University of California San Diego, La Jolla, California.
Institute for Genomic Medicine, University of California San Diego, La Jolla, California.
Alcohol Clin Exp Res. 2018 May;42(5):869-878. doi: 10.1111/acer.13623. Epub 2018 Apr 18.
Glyoxalase 1 (GLO1) is an enzyme that metabolizes methylglyoxal (MG), which is a competitive partial agonist at GABA receptors. Inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol (EtOH) drinking. This study assessed whether inhibition of GLO1, or genetic overexpression of Glo1, would also alter the locomotor effects of EtOH, which might explain reduced EtOH consumption following GLO1 inhibition. We used the prototypical GABA receptor agonist muscimol as a positive control.
Male C57BL/6J mice were pretreated with 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 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.
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.
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 GLO1 inhibition is not due to potentiation of EtOH's stimulant or depressant effects.
甘油醛 1（GLO1）是一种代谢甲基乙二醛（MG）的酶，MG 是 GABA 受体的竞争性部分激动剂。GLO1 的抑制会增加大脑中 MG 的浓度，并减少 binge-like 乙醇（EtOH）的摄入。本研究评估了 GLO1 的抑制或 Glo1 的基因过表达是否也会改变 EtOH 的运动效应，这可能解释了 GLO1 抑制后 EtOH 消耗的减少。我们使用典型的 GABA 受体激动剂 muscimol 作为阳性对照。
雄性 C57BL/6J 小鼠用 GLO1 抑制剂 S-溴苄基谷胱甘肽环戊基二酯（pBBG；7.5mg/kg；实验 1）或 muscimol（0.75mg/kg；实验 2）预处理，或用其相应的载体预处理。然后，我们确定 pBBG 或 muscimol 预处理是否改变了一系列 EtOH 剂量（0、0.5、1.0、1.5、2.0 和 2.5）对运动的反应。我们还在 FVB/NJ 野生型和转基因 Glo1 过表达小鼠中检查了一系列 EtOH 剂量对运动的反应（实验 3）。在所有 3 个实验中都评估了焦虑样行为（在开放场中心停留的时间）。
pBBG 预处理或 Glo1 转基因过表达均未改变 EtOH 的剂量反应曲线。相反，muscimol 减弱了低 EtOH 剂量的运动刺激作用，并增强了高 EtOH 剂量的运动镇静作用。在 EtOH 处理后，没有观察到药物或基因型差异在焦虑样行为方面。
本研究中使用的 pBBG 剂量在先前显示可减少 EtOH 饮酒的有效范围内。Glo1 过表达先前已显示可增加 EtOH 饮酒。然而，这两种操作都没有改变 EtOH 运动效应的剂量反应曲线，而 muscimol 似乎增强了 EtOH 的运动镇静作用。本研究数据表明，GLO1 抑制引起的 EtOH 饮酒减少不是由于增强 EtOH 的兴奋剂或抑制剂作用。
