Differential expression of miR-1249-3p and miR-34b-5p between vulnerable and resilient phenotypes of cocaine addiction.

Cocaine addiction is a complex brain disorder involving long-term alterations that lead to loss of control over drug seeking. The transition from recreational use to pathological consumption is different in each individual, depending on the interaction between environmental and genetic factors. Epigenetic mechanisms are ideal candidates to study psychiatric disorders triggered by these interactions, maintaining persistent malfunctions in specific brain regions. Here we aim to study brain-region-specific epigenetic signatures following exposure to cocaine in a mouse model of addiction to this drug. Extreme subpopulations of vulnerable and resilient phenotypes were selected to identify miRNA signatures for differential vulnerability to cocaine addiction. We used an operant model of intravenous cocaine self-administration to evaluate addictive-like behaviour in rodents based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition criteria to diagnose substance use disorders. After cocaine self-administration, we performed miRNA profiling to compare two extreme subpopulations of mice classified as resilient and vulnerable to cocaine addiction. We found that mmu-miR-34b-5p was downregulated in the nucleus accumbens of vulnerable mice with high motivation for cocaine. On the other hand, mmu-miR-1249-3p was downregulated on vulnerable mice with high levels of motor disinhibition. The elucidation of the epigenetic profile related to vulnerability to cocaine addiction is expected to help find novel biomarkers that could facilitate the interventions to battle this devastating disorder.