Cocaine disrupts stress resilience through state-dependent dopaminergic mechanisms in the nucleus accumbens.

BACKGROUND: Depression and substance use disorders frequently co-occur, yet it remains unclear whether similar depression-related behaviors reflect a common underlying neural state. Cocaine use is associated with worsening depressive symptoms, suggesting that drug exposure may interact with pre-existing behavioral states. METHODS: Male C57BL/6J and TH-Cre mice were used (n = 8-33/group, depending on experiment). Stress-resilient states were induced using electroconvulsive stimulation (ECS) or viral overexpression of ΔFosB in the nucleus accumbens (NAc). Behavioral responses were assessed using social interaction, conditioned place preference, conspecific interaction, elevated plus maze, and forced swim tests. To examine circuit mechanisms, we used retrograde Cre-dependent chemogenetic inhibition of TH-positive NAc-projecting neurons, with VTA dopaminergic projections as the primary intended target. RESULTS: ΔFosB- and ECS-induced resilient states were characterized by preserved social interaction after social defeat stress. Repeated cocaine exposure disrupted these resilient states, resulting in social avoidance, while selectively increasing forced swim test immobility in socially defeated mice. Cocaine-context conditioning was not required for the disruption of resilience, and the cocaine-associated behavioral changes were not accompanied by generalized locomotor suppression. Within the same animals, chemogenetic inhibition of TH-positive NAc-projecting neurons attenuated target-dependent social avoidance after repeated cocaine exposure. CONCLUSIONS: Cocaine can destabilize established stress resilience, and TH-positive NAc-projecting neurons contribute to the expression of cocaine-associated social avoidance. Similar social avoidance phenotypes may therefore arise from distinct underlying circuit states with differential sensitivity to modulation of TH-positive NAc-projecting neurons. These findings provide a mechanistic framework for understanding how cocaine exposure may worsen depression-related behavioral states.