Epigenetic regulation of MIR-124 under ethanol dependence and withdrawal.

Withdrawal from chronic alcohol cause the persistent molecular alteration, such as changes in the release of neurotransmitter and gene expression. The alterations are thought to increase in the risk of relapse. Recent studies suggest that the gene expression regulated by histone acetylation may play an important role in the dependence of abused drugs, including of ethanol. Furthermore, miRNA, another regulator of gene expression, are also important molecules for the dependence. However, changes in the molecules under ethanol withdrawal and its relationship are poorly understood. In the present study, we investigated the expression of acetylated histone H3 and miR-124 in mouse brain at 3 days after ethanol withdrawal. 6-Week ages of C57BL/6J mice were treated with liquid diet containing ethanol for 10 days. Using the escalating ethanol dosage schedule, the mice were fed the ethanol diet as follows: 1st day: 1 w/v%: 2nd and 3rd day: 3 w/v%; 4th and 5th day: 4 w/v% and from the 6th to 10th day: 5 w/v% ethanol diet, respectively. The pair-fed control mice were given the same volume of ethanol-free liquid diet with glucose substituted in isocaloric quantities for ethanol. After feeding alcohol liquid diet, the mice showed severe withdrawal signs. The expression of acetylated histone H3 was significantly decreased in limbic forebrain at 3 days after withdrawal. We found that miR-124 also decreased in the limbic forebrain. It has been reported that Cdc42 regulates neuronal development as a target of miR-124. We found that Cdc42 protein markedly increased in both brain regions at 3 days after withdrawal. Our findings suggest that changes in the expression of miR-124 via histone acetylation leads to change the Cdc42 expression under ethanol withdrawal.