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

Abstract

Purpose of the study: Our aims are two-fold: (1) to examine the effects of lowering dietary omega- 6 polyunsaturated fatty acids (n-6 PUFA, linoleic acid; LA) and/or supplementation of omega-3 polyunsaturated fatty acids (n-3 PUFA, eicosapentaenoic acid and docosahexaenoic acid; EPA and DHA) on voluntary ethanol binge drinking and (2) to examine the pathway networks involved in the interactions of polyunsaturated fatty acids and ethanol in brain regions involved in addiction. 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% linoleic acid or 1 en% linoleic acid) and n-3 PUFA (0.5 en%EPA+DHA or 0 en%EPA+DHA). The fatty acid compositions of diets are crafted based on contemporary American and evolutionary model intake. Male offspring continued on their respective maternal diet for 8 weeks before drinking-in-the-dark paradigm. During the 6-week ethanol binge drinking, mice were exposed to cycles of 5-day 20%v/v ethanol for 4 h in the dark and 2-day abstinence. RNASeq cohort: Same dietary interventions were applied. 14-week-oldmale offspring was subjected to a 10-day 2.5 g/kg ethanol gavage paradigm. Striatum, prefrontal cortex and cerebellum were collected for next generation RNA sequencing after the last dose of gastric gavage. Summary of results: Mice fed 1 en% LA and 0 en% EPA+DHA (L6L3) lowered voluntary ethanol binge drinking by 29% for the last 4 consecutive weeks as compared tomice fed 8 en%LA and 0 en% EPA+DHA (H6L3). 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). Panther pathway analysis showed that striatal transcriptomic signatures in response to ethanol gav age are vastly different between dietary interventions. Conclusion: 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 effective in preventing adolescent/young adult alcohol binge drinking.