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However, little is known about how antecedent behavioral characteristics, such as valuation of hedonic reinforcers prior to drug use, influence fentanyl intake trajectories. Moreover, it is unclear if distinct escalation phenotypes are driven by transcriptomic markers predictive of OUD susceptibility. Male and female Sprague-Dawley rats (n\u2009=\u200972) were trained in a sucrose reinforcement task using a progressive ratio schedule. Individual differences in responsivity to sucrose were hypothesized to predict escalation of fentanyl intake. Rats underwent daily 1-h acquisition sessions for i.v. fentanyl self-administration (2.5\u2009\u00b5g\/kg; FR1) for 7 days, followed by 21 6-h escalation sessions, then tissue from prefrontal cortex was collected for RNA sequencing and qPCR. Latent growth curve and group-based trajectory modeling were used, respectively, to evaluate the association between sucrose reinforcement and fentanyl self-administration and to identify whether distinct escalation phenotypes can be linked to gene expression patterns. Sucrose breakpoints did not predict fentanyl acquisition nor change during escalation but did predict fentanyl intake on the first day of extended access. Permutation analyses found no associations between behavior and single gene expression, either overall or within our ascertained phenotypes. However, weighted genome correlation network analysis (WGCNA) and gene set enrichment analysis (GSEA) determined several gene modules linked to escalated fentanyl intake, including genes coding for voltage-gated potassium channels, calcium channels, and excitatory synaptic signaling. Transcription factor analyses identified EZH2 and JARID2 as potential transcriptional regulators associated with escalated fentanyl intake. Further, these modules were enriched for genome-wide association study (GWAS) term categories relating to substance use disorders. Escalation of opioid intake largely differs from motivation for natural rewards like sucrose. Further, the gene networks associated with fentanyl escalation suggest that engagement of select molecular pathways were associated with \u201caddiction prone\u201d behavioral endophenotypes, potentially representing druggable targets for OUD. Our extended in silico analysis found that gene networks associated with the \u201caddiction prone\u201d high escalating rats were enriched for genes with known risk alleles for substance use disorders and identified transcription factors that may regulate these networks, highlighting the importance of integrating findings from translational preclinical models, supporting patient-centered treatment options for OUD.<\/jats:p>","DOI":"10.1038\/s41398-026-04034-1","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T15:22:51Z","timestamp":1776871371000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Behavioral and transcriptomic markers of susceptibility to escalate fentanyl intake"],"prefix":"10.1038","volume":"16","author":[{"given":"Jack","family":"Keady","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Charnigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob D.","family":"Shaykin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily R.","family":"Prantzalos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengfan","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Denehy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody","family":"Bumgardner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5309-1570","authenticated-orcid":false,"given":"Justin","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Ortinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Bardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7258-1639","authenticated-orcid":false,"given":"Jill R.","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"4034_CR1","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1007\/s002280050387","volume":"53","author":"A Vermeire","year":"1998","unstructured":"Vermeire A, Remon JP, Rosseel MT, Belpaire F, Devulder J, Bogaert MG. 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