Dataset Information

Behavioral Deficits Following Withdrawal from Chronic Ethanol Are Influenced by SLO Channel Function in Caenorhabditis elegans.

ABSTRACT: Symptoms of withdrawal from chronic alcohol use are a driving force for relapse in alcohol dependence. Thus, uncovering molecular targets to lessen their severity is key to breaking the cycle of dependence. Using the nematode Caenorhabditis elegans, we tested whether one highly conserved ethanol target, the large-conductance, calcium-activated potassium channel (known as the BK channel or Slo1), modulates ethanol withdrawal. Consistent with a previous report, we found that C. elegans displays withdrawal-related behavioral impairments after cessation of chronic ethanol exposure. We found that the degree of impairment is exacerbated in worms lacking the worm BK channel, SLO-1, and is reduced by selective rescue of this channel in the nervous system. Enhanced SLO-1 function, via gain-of-function mutation or overexpression, also dramatically reduced behavioral impairment during withdrawal. Consistent with these results, we found that chronic ethanol exposure decreased SLO-1 expression in a subset of neurons. In addition, we found that the function of a distinct, conserved Slo family channel, SLO-2, showed an inverse relationship to withdrawal behavior, and this influence depended on SLO-1 function. Together, our findings show that modulation of either Slo family ion channel bidirectionally regulates withdrawal behaviors in worm, supporting further exploration of the Slo family as targets for normalizing behaviors during alcohol withdrawal.

SUBMITTER: Scott LL

PROVIDER: S-EPMC5500142 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Behavioral Deficits Following Withdrawal from Chronic Ethanol Are Influenced by SLO Channel Function in Caenorhabditis elegans.

Scott Luisa L LL Davis Scott J SJ Yen Rachel C RC Ordemann Greg J GJ Nordquist Sarah K SK Bannai Deepthi D Pierce Jonathan T JT

Genetics 20170525 3

Symptoms of withdrawal from chronic alcohol use are a driving force for relapse in alcohol dependence. Thus, uncovering molecular targets to lessen their severity is key to breaking the cycle of dependence. Using the nematode Caenorhabditis elegans, we tested whether one highly conserved ethanol target, the large-conductance, calcium-activated potassium channel (known as the BK channel or Slo1), modulates ethanol withdrawal. Consistent with a previous report, we found that C. elegans</ ...[more]

PMID: 28546434

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Project description:The calcium-gated potassium channel SLO-1 in Caenorhabditis elegans was recently identified as key component for action of emodepside, a new anthelmintic drug with broad spectrum activity. In this study we identified orthologues of slo-1 in Ancylostoma caninum, Cooperia oncophora, and Haemonchus contortus, all important parasitic nematodes in veterinary medicine. Furthermore, functional analyses of these slo-1 orthologues were performed using heterologous expression in C. elegans. We expressed A. caninum and C. oncophora slo-1 in the emodepside-resistant genetic background of the slo-1 loss-of-function mutant NM1968 slo-1(js379). Transformants expressing A. caninum slo-1 from C. elegans slo-1 promoter were highly susceptible (compared to the fully emodepside-resistant slo-1(js379)) and showed no significant difference in their emodepside susceptibility compared to wild-type C. elegans (p = 0.831). Therefore, the SLO-1 channels of A. caninum and C. elegans appear to be completely functionally interchangeable in terms of emodepside sensitivity. Furthermore, we tested the ability of the 5' flanking regions of A. caninum and C. oncophora slo-1 to drive expression of SLO-1 in C. elegans and confirmed functionality of the putative promoters in this heterologous system. For all transgenic lines tested, expression of either native C. elegans slo-1 or the parasite-derived orthologue rescued emodepside sensitivity in slo-1(js379) and the locomotor phenotype of increased reversal frequency confirming the reconstitution of SLO-1 function in the locomotor circuits. A potent mammalian SLO-1 channel inhibitor, penitrem A, showed emodepside antagonising effects in A. caninum and C. elegans. The study combined the investigation of new anthelmintic targets from parasitic nematodes and experimental use of the respective target genes in C. elegans, therefore closing the gap between research approaches using model nematodes and those using target organisms. Considering the still scarcely advanced techniques for genetic engineering of parasitic nematodes, the presented method provides an excellent opportunity for examining the pharmacofunction of anthelmintic targets derived from parasitic nematodes.

Project description:BackgroundAlcohol is among the most commonly abused drugs worldwide. Cessation of chronic alcohol consumption can result in the appearance of withdrawal symptoms that commonly promote relapse in individuals with alcohol use disorder (AUD). Thus, preclinical models of voluntary alcohol consumption, in which animals manifest spontaneous signs of withdrawal after alcohol cessation, can be useful for studying AUD and its treatment. The intermittent two-bottle choice paradigm (I2BC) has been used extensively to examine alcohol intake in rodents. However, previous studies have reported conflicting observations regarding its potential to result in the spontaneous manifestation of withdrawal upon alcohol cessation.MethodsWe employed a battery of behavioral tests to examine the emergence of affective and physical signs of withdrawal in female and male mice exposed to alcohol in the I2BC for 10 weeks. Specifically, mice of both sexes undergoing 24-h withdrawal from the I2BC were tested for physical signs of withdrawal, anxiety-like behavior in the open field arena (OFA) and elevated plus maze (EPM), and anxiety/compulsive-like behavior in the marble burying test (MBT). The main outcomes from these tests were combined into a behavioral severity score to describe the overall behavioral phenotype.ResultsBoth female and male mice undergoing withdrawal from the I2BC displayed elevated physical signs of withdrawal and anxiety-associated behavior in the EPM and MBT. Analysis of the overall behavioral severity score revealed more severe phenotypes in female and male mice undergoing withdrawal from the I2BC than controls. Additionally, stratification of the mice based on severity scores demonstrated a differential distribution of severities between the exposure groups.ConclusionsWe confirmed that a significant fraction of mice chronically exposed to alcohol in the I2BC display spontaneous withdrawal. In addition, we showed that computing a severity score from a combination of behavioral metrics can be useful in preclinical research to model evaluation tools used in patients with AUD.

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Behavioral Deficits Following Withdrawal from Chronic Ethanol Are Influenced by SLO Channel Function in Caenorhabditis elegans.

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Behavioral Deficits Following Withdrawal from Chronic Ethanol Are Influenced by SLO Channel Function in <i>Caenorhabditis elegans</i>.

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