The Omega-3 Fatty Acid Eicosapentaenoic Acid Is Required for Normal Alcohol Response Behaviors in C. elegans

Abstract

Alcohol addiction is a widespread societal problem, for which there are few treatments. There are significant genetic and environmental influences on abuse liability, and understanding these factors will be important for the identification of susceptible individuals and the development of effective pharmacotherapies. In humans, the level of response to alcohol is strongly predictive of subsequent alcohol abuse. Level of response is a combination of counteracting responses to alcohol, the level of sensitivity to the drug and the degree to which tolerance develops during the drug exposure, called acute functional tolerance. We use the simple and well-characterized nervous system of Caenorhabditis elegans to model the acute behavioral effects of ethanol to identify genetic and environmental factors that influence level of response to ethanol. Given the strong molecular conservation between the neurobiological machinery of worms and humans, cellular-level effects of ethanol are likely to be conserved. Increasingly, variation in long-chain polyunsaturated fatty acid levels has been implicated in complex neurobiological phenotypes in humans, and we recently found that fatty acid levels modify ethanol responses in worms. Here, we report that 1) eicosapentaenoic acid, an omega-3 polyunsaturated fatty acid, is required for the development of acute functional tolerance, 2) dietary supplementation of eicosapentaenoic acid is sufficient for acute tolerance, and 3) dietary eicosapentaenoic acid can alter the wild-type response to ethanol. These results suggest that genetic variation influencing long-chain polyunsaturated fatty acid levels may be important abuse liability loci, and that dietary polyunsaturated fatty acids may be an important environmental modulator of the behavioral response to ethanol.

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

“…Although we do not yet know the relevant targets of SWI/SNF regulation for ethanol-response behaviors, we have identified several genes that regulate initial sensitivity and AFT in worms that are excellent candidates for regulation by SWI/SNF, including the large conductance voltage and calcium sensitive potassium (BK) channel and genes that regulate lipid metabolism and utilization in the animal (23,24,46). Variation in SWI/SNF components may influence these and/or other as-yet-unidentified downstream mediators of the behavioral response to ethanol.…”

Role of CYP eicosanoids in the regulation of pharyngeal pumping and food uptake in Caenorhabditis elegans

“…For the or fat-3 ( ⌬ -6 fatty acid desaturase) cause C20-PUFA defi ciency and lead to defi cits in movement, defecation cycle, pharyngeal pumping activity, basal innate immunity, and growth ( 10 ). Almost all of these impairments are rather functional than developmental and can be rescued by feeding the mutant worms with AA and/or EPA ( 8,(11)(12)(13).…”

A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect inCaenorhabditis elegans

“…Mutations in multiple genes have previously been shown to generate altered phenotypes compared to wild-type animals upon treatment with ethanol (Davies et al 2003(Davies et al , 2004Kayser et al 2003;Kapfhamer et al 2008;Graham et al 2009;Speca et al 2010;Bettinger et al 2012;Bhandari et al 2012;Jee et al 2013;Raabe et al 2014). We examined two of these genes that have robust mutant ethanol response phenotypes, slo-1 and npr-1.…”

“…Ethanol also produces disinhibition of certain crawling behaviors that would normally be inhibited in a liquid environment (Topper et al 2014). Acute functional tolerance, which is unrelated to metabolism of the drug, develops rapidly to the effects of ethanol on the speed of locomotion (Davies et al 2004;Bettinger et al 2012;Raabe et al 2014). Longer ethanol exposures followed by removal from the drug can lead to withdrawal-related phenotypes (Davies et al 2004;Mitchell et al 2010).…”