Extinction of Nicotine and Cocaine Seeking in Rats Reveals Novel, Unique and Time-Dependent Molecular Adaptations in the Medial Prefrontal Cortex

Nicotine dependence is characterized by high relapse rates compared to other addictive substances, yet the molecular mechanisms underlying relapse vulnerability during early abstinence remain poorly understood. Here we provide the first integrated transcriptomic and epigenomic profile of nicotine extinction in the medial prefrontal cortex (mPFC). Using RNA-seq and ATAC-seq at 1 and 6 days after nicotine or cocaine self-administration, we uncovered a dynamic and drug-specific molecular response. Nicotine was associated with minimal changes at day 1 but robust transcriptional and chromatin remodelling at day 6, possibly consistent with incubation of craving. Notably, we identified sustained upregulation of the dual specificity phosphatase Dusp4 (first report in nicotine), implicating compensatory regulation of MAPK signalling in abstinence-related plasticity. Chromatin accessibility changes were enriched in intergenic regions containing FOS and JUND motifs, possibly indicative of enhancer-mediated transcriptional control rather than promoter remodelling. Together, these findings highlight nicotine-specific, time-dependent molecular adaptations in the mPFC and identify MAPK phosphatase signalling and enhancer activity as potential targets for relapse prevention during early abstinence.