Sex-specific vulnerability to cannabinoid addiction-like behavior and associated miRNA signatures in a WIN 55,212-2 self-administration mouse model

Cannabis is one of the most widely used psychoactive substances worldwide, and cannabis use disorder (CUD) is increasingly recognized as a major public health concern. Clinical evidence indicates that women may be particularly vulnerable to developing addiction, exhibiting a faster transition from initial drug use to loss of control and increased relapse vulnerability. However, females remain underrepresented in both preclinical and clinical research, limiting our understanding of the neurobiological mechanisms underlying this susceptibility. Here, we investigated sex differences in behavioral and epigenetic susceptibility to cannabinoid addiction using a mouse operant self-administration model with the synthetic cannabinoid agonist WIN 55,212-2. Female mice displayed increased addiction-like behavior, characterized by greater persistence of responding during drug-free periods and enhanced compulsive-like drug seeking compared to males. miRNA profiling in the medial prefrontal cortex (mPFC) identified a female-specific epigenetic signature associated with the addiction-like phenotype, including downregulation of mmu-miR-669j, mmu-miR-7036b-5p, mmu-miR-878-3p, and mmu-miR-7017-3p, together with upregulation of mmu-miR-3092-5p in addicted females. Functional enrichment analyses of predicted target genes revealed pathways related to synaptic organization, axon guidance, neurotransmission, and structural plasticity. Together, these findings demonstrate sex-dependent differences in vulnerability to cannabinoid addiction-like behavior and identify a specific miRNA signature in the mPFC associated with this phenotype, highlighting potential targets for the development of sex-specific therapeutic strategies.