Abstract
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 (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 acute ethanol withdrawal. Following an injection of 4 g/kg alcohol, both B6 and FVB mice overexpressing Glo1 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 (S-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.
Highlights
Alcohol withdrawal is a key feature of alcohol dependence and includes physiological and affective symptoms, such as tremors, nausea, vomiting, irritability, insomnia, and anxiety
We showed that the overexpression of the gene glyoxalase 1 (Glo1) can produce increased ethanol withdrawal severity, as assessed using handling-induced convulsions (HICs)
The treatment of wild-type animals with a glyoxalase 1 (GLO1) inhibitor had the opposite effect, namely, attenuating ethanol withdrawal seizure severity in mice undergoing a chronic ethanol exposure procedure. These results provide evidence that GLO1 activity modulated Central nervous system (CNS) hyperexcitability during ethanol withdrawal in mice
Summary
Alcohol (ethanol) withdrawal is a key feature of alcohol dependence and includes physiological and affective symptoms, such as tremors, nausea, vomiting, irritability, insomnia, and anxiety. There is considerable evidence from both human and model organism studies for genetic contributions to ethanol withdrawal severity [9,10,11,12,13]. Gene polymorphisms associated with many neurotransmitter systems have been explored in relation to ethanol withdrawal (for a review, see [8]). Several of these candidate genes and association studies have identified relationships between specific genetic variants and ethanol withdrawal severity [14,15,16,17,18]. Animal models are a useful complementary tool for studying novel genetic contributions to ethanol-related traits, since animal models can isolate specific aspects of ethanol withdrawal, such as seizure susceptibility. The heritability of susceptibility to ethanol withdrawal seizures has been well-established in mouse models: inbred mouse strains and recombinant inbred panels show a high degree of phenotypic variation for this trait [11,19,20,21], and selective breeding has produced withdrawal-seizure-prone and resistant lines of mice [10,22]
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