Abstract
The severity of withdrawal from chronic ethanol is a driving force for relapse in alcohol dependence. Thus, uncovering molecular changes that can be targeted to lessen withdrawal symptoms is key to breaking the cycle of dependence. Using the model nematode Caenorhabditis elegans, we tested whether one highly conserved ethanol target, the BK potassium channel, may play a major role in alcohol withdrawal. Consistent with a previous report, we found that C. elegans displays behavioral impairment during withdrawal from chronic ethanol that can be reduced by low-dose ethanol. We discovered that the degree of impairment is exacerbated in worms lacking the BK channel, SLO-1, and is alleviated by selective rescue of the BK channel in the nervous system. Conversely, behavioral impairment during withdrawal was dramatically lower in worms with BK channel function enhanced via gain-of-function mutation or overexpression. Consistent with these results, we found that chronic ethanol exposure decreased BK channel expression in a subset of neurons. In addition, we found that a distinct, conserved large-conductance potassium channel, SLO-2, showed the inverse functional relationship, influencing withdrawal behavior via a SLO-1 channel-dependent mechanism. Our findings demonstrate that withdrawal symptoms in C. elegans are mechanistically explained in part by a functional imbalance in the nervous system associated with a reduction in SLO-1 channel expression. Therefore, selective modulation of Slo family ion channel activity may represent a novel therapeutic approach to explore for normalizing behaviors during alcohol withdrawal.
ARTICLE SUMMARY People addicted to alcohol maintain maladaptive drinking patterns in part to avoid the terrible symptoms of withdrawal. It is unclear whether any single molecule may be genetically modified to alleviate withdrawal symptoms. Here, we discover that for the nematode C. elegans, upregulating function of the conserved BK potassium channel SLO-1 prevents alcohol withdrawal symptoms. Conversely, downregulating SLO-1 channel function makes withdrawal worse. Moreover, we identify an inverse relation between SLO-1 and a second type of BK channel named SLO-2 in the severity of withdrawal. The BK channel thus represents an attractive molecular target to consider for alleviating alcohol withdrawal symptoms.
Statement on data and reagent availability Strains are available upon request or through the Caenorhabditis Genetics Center.
