Dietary Lowering of omega-6 Polyunsaturated Fatty Acids Lowered Voluntary Ethanol Binge-drinking in Mice (OR19-02-19)

Abstract

Abstract Objectives Our objective is to examine the effects of lowering dietary omega-6 polyunsaturated fatty acids (n-6 PUFA, linoleic acid; LA) and/or supplementation of omega-3 PUFA (n-3 PUFA, eicosapentaenoic acid and docosahexaenoic acid; EPA and DHA) on voluntary ethanol binge drinking and pathway networks involved in the interactions of PUFA and ethanol in mesolimbic circuit of the brain. Methods Behavioral cohort: Time-pregnant C57BL/6J dams were randomized to one of four custom dietary interventions. The diets varied in the combination of n-6 PUFA (8 energy% LA or 1 en% LA) and n-3 PUFA (0.5 en% EPA + DHA or 0 en% EPA + DHA). The dietary fatty acid compositions are crafted based on contemporary American and evolutionary model intake. Male offspring continued their respective maternal diet for 8 weeks before ethanol exposure. During the 6-week ethanol binge drinking, mice were exposed to cycles of 5-day 20%v/v ethanol for 4 hours in the dark and 2-day abstinence. RNA-Sequencing cohort: Same dietary interventions were applied. 15-week-old male offspring was subjected to a 9-day 2 g/kg and 1-day 5 g/kg ethanol gavage paradigm. Striatum were collected for next generation RNA sequencing after the last dose of gastric gavage. Results Mice fed 1 en% LA and 0 en% EPA + DHA (L6L3) lowered voluntary ethanol binge drinking by 29% as compared to mice fed 8 en% LA and 0 en% EPA + DHA (H6L3) (one-way ANOVA; week 3, p = 0.0072; week 4–6, P < 0.05). Mice fed 1 en% LA and 0.5 en% EPA + DHA (L6H3) or 8 en% LA and 0.5 en% EPA + DHA (H6H3) did not differ in ethanol binge drinking as compared to L6L3 and H6L3 mice. Mice fed L6L3 exhibited more differentially expressed genes in striatum as compared to other dietary interventions (L6L3, 158 genes; H6L3, 16; L6H3, 39; H6H3, 20). Gene set analysis by Panther showed that striatal transcriptomic signatures in response to ethanol gavage are vastly different between dietary interventions. Conclusions Dietary fatty acids may alter striatal transcriptomic response to ethanol which may result in lowering of voluntary ethanol binge drinking. Dietary lowering of n-6 PUFA may be an effective strategy in preventing voluntary alcohol binge drinking which is a major public health concern. Funding Sources National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Section of Nutritional Neuroscience.