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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\n                    <jats:italic>Dusp4<\/jats:italic>\n                    (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.\n                  <\/jats:p>","DOI":"10.1007\/s10571-026-01667-0","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T04:14:08Z","timestamp":1768364048000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Extinction of Nicotine and Cocaine Seeking in Rats Reveals Novel, Unique and Time-Dependent Molecular Adaptations in the Medial Prefrontal Cortex"],"prefix":"10.1007","volume":"46","author":[{"given":"Caspar","family":"Muenstermann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah J.","family":"Baracz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eilish C.","family":"Heffernan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas C.","family":"Lister","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul D.","family":"Waters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly J.","family":"Clemens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"1667_CR1","unstructured":"Andrews S (2010) A Quality Control Tool for High Throughput Sequence Data [Online]. http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/"},{"issue":"2","key":"1667_CR2","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders S, Pyl PT, Huber W (2015) HTSeq\u2013a python framework to work with high-throughput sequencing data. 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