Abstract Background Early-life stress constitutes a major risk factor for the development of neuropsychiatric and substance use disorders, exerting enduring effects on stress responsivity and emotional behavior. Maternal deprivation (MD) is a well-established model of early adversity that induces persistent neurobiological alterations. During adolescence, alcohol exposure presents an additional challenge that may interact with early-life stress, potentially influencing long-term adaptations in a sex-dependent manner. Among the systems involved, lipid signaling pathways, including the endocannabinoid system (ECS) and lysophosphatidic acid (LPA) signaling, have emerged as key regulators of stress adaptation. Methods Male and female Wistar rats were subjected to a single 24-h MD episode on postnatal day 9 (PND9). During adolescence (PND31–55), animals received intermittent alcohol exposure (3 g/kg) or saline. Behavioral assessments included the forced swim test and elevated plus maze. Plasma levels of corticosterone, monoacylglycerols, N-acylethanolamines, LPA, and autotaxin were measured. Concurrently, mRNA expression of genes encoding ECS- and LPA-related receptors, as well as enzymes involved in the metabolism of these lipid signaling pathways, was analyzed in the medial prefrontal cortex (mPFC). Data were evaluated using three-way ANOVA with sex, MD, and adolescent alcohol exposure as factors. Results MD induced persistent metabolic alterations and revealed sex-specific effects on alcohol pharmacokinetics, with increased blood alcohol concentrations in MD females. Behavioral analyses demonstrated sex-dependent effects, with MD increasing active coping in males and decreasing it in females, while enhancing open-arm exploration independently of adolescent alcohol exposure. Adolescent alcohol exposure increased plasma corticosterone levels. MD and sex significantly altered circulating lipid mediators, showing opposite patterns in males and females. Additionally, MD and adolescent alcohol exposure differentially modulated the expression of ECS- and LPA-related genes in the mPFC, indicating sex-dependent molecular adaptations. Conclusions Early-life stress establishes long-lasting, sex-specific alterations in behavioral and lipid-mediated stress responses. Adolescent alcohol exposure acts as a secondary challenge, unmasking or amplifying these adaptations. The integration of peripheral lipid profiles with mPFC molecular changes highlights lipid signaling pathways as key mediators linking early adversity and adolescent experiences with long-term vulnerability to stress-related psychopathology.
Sanchez-Marin et al. (Sun,) studied this question.