Oleoylethanolamide effects on stress-induced ethanol consumption: A lipid at the crossroads between stress, reward and neuroinflammation

The endocannabinoid system is involved in multiple drug-related behaviors and the transient increase in endogenous cannabinoids and endocannabinoid-like molecules contributes to healthy adaptation to stress exposure. Oleoylethanolamide (OEA) belongs to the N-acylethanolamines and interacts with the endocannabinoid system. In this study, we investigated the effect of systemic OEA treatment (10 mg/kg), before or after social defeat (SD), on ethanol self-administration (SA). Mice were divided into non-stressed (EXP) and stressed (SD) groups and randomly assigned to a treatment condition (control-CTRL, OEA or 10OEA). The EXP/SD-OEA group of mice received four doses of OEA before each SD encounter, while mice in the EXP/SD-10OEA group received a daily dose for 10 consecutive days following stress exposure. Three weeks after SD, mice were trained to self-administer a 20 % (vol/vol) ethanol solution. Upon extinction, a cue-induced reinstatement test was performed. Our results showed that both OEA treatments effectively prevented the stress-induced increase in ethanol consumption observed in defeated mice. No significant effects of OEA on relapse-like behavior were observed. Additionally, we found that animals exposed to OEA during SD encounters showed reduced nuclear factor kappa B (NF-κB) levels, suggesting an anti-inflammatory effect of OEA, while tumor necrosis factor (TNFα) gene expression decreased in defeated animals. In summary, these findings suggest that exogenously increasing OEA levels counteracts the adverse effects of stress on ethanol drinking while having some impact on inflammatory patterns.