A novel cholinergic action of alcohol and the development of tolerance to that effect in Caenorhabditis elegans

Edward G. Hawkins, Ian Martin, Lindsay M. Kondo, Meredith E. Judy, Victoria E. Brings, Chung Lung Chan, Ginamari G. Blackwell, Jill C. Bettinger, Andrew G. Davies

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Understanding the genes and mechanisms involved in acute alcohol responses has the potential to allow us to predict an individual’s predisposition to developing an alcohol use disorder. To better understand the molecular pathways involved in the activating effects of alcohol and the acute functional tolerance that can develop to such effects, we characterized a novel ethanolinduced hypercontraction response displayed by Caenorhabditis elegans. We compared body size of animals prior to and during ethanol treatment and showed that acute exposure to ethanol produced a concentration-dependent decrease in size followed by recovery to their untreated size by 40 min despite continuous treatment. An increase in cholinergic signaling, leading to muscle hypercontraction, is implicated in this effect because pretreatment with mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, blocked ethanol-induced hypercontraction, as did mutations causing defects in cholinergic signaling (cha-1 and unc-17). Analysis of mutations affecting specific subunits of nAChRs excluded a role for the ACR-2R, the ACR-16R, and the levamisole-sensitive AChR and indicated that this excitation effect is dependent on an uncharacterized nAChR that contains the UNC-63 a-subunit. We performed a forward genetic screen and identified eg200, a mutation that affects a conserved glycine in EAT-6, the a-subunit of the Na+/K+ ATPase. The eat-6(eg200) mutant fails to develop tolerance to ethanol-induced hypercontraction and remains contracted for at least 3 hr of continuous ethanol exposure. These data suggest that cholinergic signaling through a specific a-subunit-containing nAChR is involved in ethanol-induced excitation and that tolerance to this ethanol effect is modulated by Na+/K+ ATPase function.

Original languageEnglish (US)
Pages (from-to)135-149
Number of pages15
JournalGenetics
Volume199
Issue number1
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'A novel cholinergic action of alcohol and the development of tolerance to that effect in Caenorhabditis elegans'. Together they form a unique fingerprint.

  • Cite this

    Hawkins, E. G., Martin, I., Kondo, L. M., Judy, M. E., Brings, V. E., Chan, C. L., Blackwell, G. G., Bettinger, J. C., & Davies, A. G. (2015). A novel cholinergic action of alcohol and the development of tolerance to that effect in Caenorhabditis elegans. Genetics, 199(1), 135-149. https://doi.org/10.1534/genetics.114.171884