Stress, reward and neuroinflammation: Oleoylethanolamide effects on stress-induced ethanol consumption in female mice

Stress is a major contributor to psychiatric disorders and alcohol use, conditions commonly associated with increased neuroinflammation. Oleoylethanolamide (OEA), an endogenous lipid mediator with anti-inflammatory properties, reduces alcohol intake and stress-related behaviors in male rodents; however, its effects in females remain underexplored. This study investigated whether OEA attenuates vicarious social defeat stress (VSD)–induced increases in ethanol consumption and neuroinflammatory markers in female mice. Animals were assigned to stressed (VSD) or non-stressed (EXP) conditions and received saline (SAL), OEA prior to stress, daily OEA following stress (10OEA), or OEA administered after each ethanol drinking sessions (OEADID). Anxiety- and depressive-like behaviors were assessed one week post-VSD, followed by two weeks of Drinking in the Dark (DID) to measure ethanol intake. Neuroinflammatory markers were quantified using ELISA for CX3CL1 and IL-6 in the hippocampus and striatum, and qPCR for Il-6, Tnf, Nf-κB, Tlr4, Cnr1, Crf , and Oprm1 in the prefrontal cortex. Animals were assigned to stressed (VSD) or non-stressed (EXP) conditions and received saline (SAL), OEA prior to stress, daily OEA following stress (10OEA), or OEA administered after each ethanol drinking sessions (OEADID). Anxiety- and depressive-like behaviors were assessed one week post-VSD, followed by two weeks of Drinking in the Dark (DID) to measure ethanol intake. VSD induced weight loss, elevated corticosterone levels, increased locomotor activity, and reduced grooming behavior, which were not reversed by OEA. However, VSD-induced increases in ethanol intake were significantly reduced by all OEA treatments. Stress decreased CX3CL1 in the striatum and hippocampus and altered IL-6 levels regionally; OEA normalized these alterations on inflammation mediators. Additionally, stress-related changes in prefrontal inflammatory and stress-related gene expression were restored by OEA. These findings suggest that OEA may exert a protective effect against stress-induced increases in ethanol intake and attenuate the associated neuroinflammatory response in female mice, supporting its potential as a therapeutic strategy to reduce alcohol vulnerability following social stress.