Lipid Environment Modulates the Development of Acute Tolerance to Ethanol in Caenorhabditis elegans

Authors

Jill C. Bettinger, Virginia Commonwealth University, University of California San FranciscoFollow
Kapo Leung, Virginia Commonwealth University
Mia H. Bolling, Virginia Commonwealth University
Andrew D. Goldsmith, University of California - San Francisco
Andrew G. Davies, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2012

Journal/Book/Conference Title

PLOS ONE

Volume

7

DOI of Original Publication

10.1371/journal.pone.0035192

Comments

Originally published at: http://dx.doi.org/10.1371/journal.pone.0035192

Date of Submission

November 2014

Abstract

The development of tolerance to a drug at the level of the neuron reflects a homeostatic mechanism by which neurons respond to perturbations of their function by external stimuli. Acute functional tolerance (AFT) to ethanol is a fast compensatory response that develops within a single drug session and normalizes neuronal function despite the continued presence of the drug. We performed a genetic screen to identify genes required for the development of acute functional tolerance to ethanol in the nematode C. elegans. We identified mutations affecting multiple genes in a genetic pathway known to regulate levels of triacylglycerols (TAGs) via the lipase LIPS-7, indicating that there is an important role for TAGs in the development of tolerance. Genetic manipulation of lips-7 expression, up or down, produced opposing effects on ethanol sensitivity and on the rate of development of AFT. Further, decreasing cholesterol levels through environmental manipulation mirrored the effects of decreased TAG levels. Finally, we found that genetic alterations in the levels of the TAG lipase LIPS-7 can modify the phenotype of gain-of-function mutations in the ethanol-inducible ion channel SLO-1, the voltage- and calcium-sensitive BK channel. This study demonstrates that the lipid milieu modulates neuronal responses to ethanol that include initial sensitivity and the development of acute tolerance. These results lend new insight into studies of alcohol dependence, and suggest a model in which TAG levels are important for the development of AFT through alterations of the action of ethanol on membrane proteins.

Rights

© 2012 Bettinger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Pharmacology and Toxicology Publications