Background: Stress is a major risk factor for the development of depression, anxiety, and addiction. One of the most widely used animal models to study the effects of social stress is the social defeat (SD) procedure. Few studies have examined whether environmental enrichment (EE) effectively mitigates the increase in cocaine's conditioned rewarding effects induced by SD. Furthermore, the impact of EE on stress-induced depressive- and anxiety-like behaviors remains largely unexplored.

Methodology: Adolescent C57BL/6 mice were housed under either standard or enriched conditions from adolescence until the final SD session (PND 56). Depressive-like and anxiety-like behaviors were assessed using the social interaction test (SIT) and the elevated plus maze (EPM), respectively. On PND 77, conditioned place preference (CPP) was evaluated using a subthreshold dose of cocaine (1.5 mg/kg).

Results: EE did not modify coping strategies during SD but significantly reduced the proportion of mice displaying depressive-like behaviors (67% in standard housing vs. 47% in enriched housing). However, EE did not attenuate the increase in anxiety induced by SD. Notably, only socially defeated mice housed under standard conditions developed cocaine-induced CPP, confirming the protective effects of EE against drug reward vulnerability.

Conclusion: Our findings indicate that environmental enrichment during adolescence acts as an effective protective factor, promoting resilience against stress-induced vulnerability to drug reward and depression did not significantly affect anxiety-like behavior.

Acknowledgements: This work was supported by the following grants: PROMETEO (CIPROM/2021/080); PID-2020-112672RB-100; and RIAPAd RD21/0009/0005