IMPACT OF DHA SUPPLEMENTATION ON BEHAVIORAL FLEXIBILITY FOLLOWING ADOLESCENT INTERMITTENT ETHANOL EXPOSURE IN ADULT MICE

Alcohol is frequently consumed by adolescents in a binge-like pattern, which has been associated with long-term executive dysfunction and reduced behavioral flexibility. Given that adolescent intermittent ethanol (AIE) exposure disrupts neuroplasticity and increases neuroinflammation in prefrontal circuits, this study examined whether AIE induces persistent deficits in behavioral flexibility and evaluated the potential of docosahexaenoic acid (DHA) supplementation, an omega-3 fatty acid critical for synaptic function and executive processes, to ameliorate these impairments. Male and female C57BL/6J mice underwent a 4-week "Drinking-in-the-Dark" (DID) protocol (4 days/week) during adolescence, followed by DHA-enriched fish oil (700 mg/kg) or sunflower oil via gavage (3 times/week) for 8 weeks. In adulthood, behavioral flexibility was assessed using the Attentional Set-Shifting Task (AST). Results showed that while AIE did not impair initial discriminative learning, it significantly disrupted task retention, evidenced by increased trials to reach criterion and higher active errors. Notably, DHA supplementation improved initial stimulus acquisition across all groups and successfully rescued AIE-induced deficits in retention memory. However, no significant effects of AIE or DHA treatment were observed during reversal learning, nor were intradimensional or extradimensional set-shifts altered. These findings suggest that adolescent binge drinking induces specific deficits in prefrontal-dependent rule retention, rather than a generalized deficit in reversal learning or set-shifting. DHA supplementation represents a viable strategy to mitigate long-term impairment in memory retention and cognitive acquisition resulting from adolescent alcohol misuse.
(This work was supported by the Grant PID2021-128650NA-I00 funded by MCIN/AEI/ 10.13039/501100011033; PPIT-UAL, Junta de Andalucía-ERDF 2021-2027. Objective RSO1.1. Programme: 54.A.).