April 20, 2021

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

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 be identified. The gene glyoxalase 1 (Glo1) 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 Glo1 on different genetic backgrounds (C57BL/6J [B6] and FVB/NJ [FVB]) were tested for handling induced convulsions (HICs) as a measure of CNS hyperexcitability during acute ethanol withdrawal. During withdrawal from an acute injection of 4 g/kg alcohol, both B6 and FVB mice overexpressing Glo1 showed increases in HICs from their wild type littermates. 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 vehicle or a GLO1 inhibitor (S-bromobenzylglutathione cyclopentyl diester [pBBG]). Treatment with pBBG reduced seizure activity, although this effect was only statistically significant following two 10-day cycles of ethanol exposure and withdrawal. Taken together, these results provide converging genetic and pharmacological evidence that GLO1 can mediate ethanol withdrawal seizure susceptibility. We discuss the likely role of the GLO1 substrate, methylglyoxal, acting as an agonist at GABA-A receptors.

 bioRxiv Subject Collection: Neuroscience

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