Intermittent and limited exposure to a high-fat diet prevents social defeat-induced increase in ethanol intake and neuroinflammation

Abstract

Social stress is widely recognized for increasing ethanol consumption, an effect mediated by an enhanced neuroinflammatory response. High-fat diets (HFDs) alleviate stress and have been shown to reduce cocaine-seeking behavior, likely by serving as an alternative reinforcer. This study examines whether intermittent HFD administration following social defeat (SD) mitigates long-term increases in ethanol (EtOH) consumption and neuroinflammatory responses in adult male mice. Two intermittent HFD protocols were tested: HFD1 × 2 (one-hour access twice a week), and HFD2 × 3 (two-hour access three times a week), initiated immediately after the last SD episode and maintained through the drinking-in-the-dark (DID) protocol. Defeated mice were categorized as resilient or susceptible using the social interaction test (SIT). At the end of the procedure, gene expression analysis of neuroinflammatory markers was conducted in the hippocampus and striatum. Intermittent HFD did not increase body weight, despite promoting binge-eating behavior. As expected, only susceptible SD mice on a standard diet (STD) showed increased ethanol consumption, whereas those on either HFD protocol consumed ethanol at levels comparable to non-stressed controls. Elevated Il-6 and Tnfα levels, along with mitochondrial dysfunction, were observed in the hippocampus and striatum of STD-fed defeated mice but were entirely absent in HFD-fed mice. These findings suggest that intermittent HFD access effectively prevents stress-induced ethanol consumption and neuroinflammatory alterations. Limited HFD access may represent a promising nutritional strategy to counteract stress-related alcohol use disorders.