In a related experiment in mice, we examined levels of phosphorylated MEK, an upstream activator of ERK, in the striatum of ethanol-naïve AlkKO mice. Interestingly, we found a 41% increase in MEK phosphorylation in this brain region (Figure S3). Increased expression of genes in the ERK pathway has been demonstrated in mouse lines selectively bred for high ethanol-preference [41]. Our data in the AlkKO mice might suggest that increased ERK signaling could be responsible for the increased ethanol consumption in these mice. Whether ALK normally inhibits ERK activation in the striatum, or whether increased MEK phosphorylation is due to compensatory changes in the AlkKO mice is a subject for future investigation. Our data, combined with the findings in ethanol-preferring mice, suggest that treatment with MEK inhibitors might be a potential therapeutic strategy for excessive ethanol consumption and AUDs. Faccidomo et al. tested the MEK inhibitor SL 327 for ethanol self-administration in C57BL/6 mice and observed a biphasic response to MEK inhibition [42]. Low doses increased operant responding for ethanol, while high doses decreased responding. Ethanol induces c-fos expression, an effect
