STRUCTURAL SIGNATURES OF COCAINE ADDICTION-LIKE BEHAVIOR IN RATS

Cocaine is one of the most widely consumed illicit substances, yet only a fraction of regular users develops cocaine use disorder (CUD). It is still unclear which biological factors drive resilience and vulnerability to CUD. The present study addresses this question by combining multimodal MRI with a clinically informed rat model of CUD – the 0/3Crit model. In this paradigm, rats undergo prolonged cocaine self-administration before stratification according to different behavioral dimensions. We employed longitudinal voxel-based morphometry and diffusion tensor imaging to quantify structural brain differences between 48 resilient and vulnerable Sprague Dawley rats across cocaine self-administration. No significant baseline differences were observed. However, addiction-prone rats exhibited earlier and more widespread increases in frontostriatal gray matter volume relative to resilient animals. In several affected regions, gray matter volume correlated with addiction-like behavior after prolonged cocaine self-administration, indicating functional relevance of these effects. In contrast, resilient rats displayed decreases in mean diffusivity in several white matter tracts, whereas vulnerable rats did not differ from controls, pointing to phenotype-specific responses to cocaine exposure. These findings imply divergent trajectories in response to prolonged cocaine self-administration, comprising stronger frontostriatal hypertrophy in vulnerable animals and distinct microstructural remodeling in resilient rats, suggesting that resilience to CUD involves qualitative differences in neurobiological adaptation rather than merely attenuated change in response to cocaine.