Barkley-Levenson Amanda M, Lee Amy, Palmer Abraham A
Department of Psychiatry, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA.
Institute for Genomic Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA.
Brain Sci. 2021 Jan 19;11(1):127. doi: 10.3390/brainsci11010127.
Central nervous system (CNS) hyperexcitability is a clinically significant feature of acute ethanol withdrawal. There is evidence for a genetic contribution to withdrawal severity, but specific genetic risk factors have not been identified. The gene glyoxalase 1 () has been previously implicated in ethanol consumption in mice, and GLO1 inhibition can attenuate drinking in mice and rats. Here, we investigated whether genetic and pharmacological manipulations of GLO1 activity can also mediate ethanol withdrawal seizure severity in mice. Mice from two transgenic lines overexpressing on different genetic backgrounds (C57BL/6J (B6) and FVB/NJ (FVB)) were tested for handling-induced convulsions (HICs) as a measure of acute ethanol withdrawal. Following an injection of 4 g/kg alcohol, both B6 and FVB mice overexpressing showed increases in HICs compared to wild-type littermates, though only the FVB line showed a statistically significant difference. We also administered daily ethanol injections (2 g/kg + 9 mg/kg 4-methylpyrazole) to wild-type B6 mice for 10 days and tested them for HICs on the 10th day following treatment with either a vehicle or a GLO1 inhibitor (-bromobenzylglutathione cyclopentyl diester (pBBG)). Treatment with pBBG reduced HICs, although this effect was only statistically significant following two 10-day cycles of ethanol exposure and withdrawal. These results provide converging genetic and pharmacological evidence that GLO1 can mediate ethanol withdrawal seizure susceptibility.
中枢神经系统（CNS）的过度兴奋是急性乙醇戒断的一个具有临床意义的特征。有证据表明遗传因素对戒断严重程度有影响，但尚未确定具体的遗传风险因素。此前有研究表明，乙二醛酶1（GLO1）基因与小鼠的乙醇摄入有关，抑制GLO1可减少小鼠和大鼠的饮酒量。在此，我们研究了对GLO1活性进行基因和药理学调控是否也能介导小鼠乙醇戒断性癫痫发作的严重程度。对来自两个在不同遗传背景（C57BL/6J（B6）和FVB/NJ（FVB））下过表达GLO1的转基因品系的小鼠进行处理诱导惊厥（HICs）测试，以此作为急性乙醇戒断的指标。注射4 g/kg酒精后，与野生型同窝小鼠相比，过表达GLO1的B6和FVB小鼠的HICs均增加，不过只有FVB品系显示出统计学上的显著差异。我们还对野生型B6小鼠每日注射乙醇（2 g/kg + 9 mg/kg 4 - 甲基吡唑），持续10天，并在第10天用溶剂或GLO1抑制剂（-溴苄基谷胱甘肽环戊基二酯（pBBG））处理后测试它们的HICs。pBBG处理可减少HICs，尽管这种效应仅在经过两个10天的乙醇暴露和戒断周期后才具有统计学意义。这些结果提供了一致的遗传和药理学证据，表明GLO1可介导乙醇戒断性癫痫发作的易感性。
