Nucleus Accumbens Alterations Linked to Stress-Induced Vulnerability to Cocaine Addiction in Preclinical Models: A Scoping Review

Exposure to stress is known to modulate vulnerability to cocaine use; however, the preclinical evidence in this field remains heterogeneous and lacks a systematic synthesis. We conducted a scoping review to map the neurobiological changes in the nucleus accumbens (NAc) associated with this vulnerability. We searched PubMed combining terms for stress, NAc, and cocaine, obtaining 294 results that, after a three-stage screening process, were narrowed down to 35 studies in adult rodents (1991-2025), which assessed behavioral sensitization, conditioned place preference, or self-administration. The effects of stress depended on its duration, predictability, and controllability: moderate stressors enhanced reactivity to cocaine, whereas chronic and uncontrollable stress produced opposite effects, consistent with an anhedonic-like phenotype. The NAc emerged as a convergence node where dopaminergic, glutamatergic, and serotonergic systems are reconfigured by stress. The mechanisms with the strongest causal support were: glial neuroinflammation-driven suppression of GLT-1 and cofilin-mediated actin cytoskeleton reorganization in the NAc core, loss of inhibitory control of VTA dopaminergic neurons projecting to the NAc, and activation of dynorphin/KOR signaling in the NAc medial shell. However the underrepresentation of females (4/35 studies) and methodological heterogeneity limit the generalizability of these findings.