{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:02:06Z","timestamp":1785402126157,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,21]]},"group-title":"Animal Behavior and Cognition","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01 DA056602"],"award-info":[{"award-number":["R01 DA056602"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30 DA060810"],"award-info":[{"award-number":["P30 DA060810"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The use of fentanyl and other opioids during pregnancy is a pressing public health issue due to its association with Neonatal Opioid Withdrawal Syndrome (NOWS) and long-term neurobehavioral deficits. Human epidemiologic studies are confounded by both genetic and environmental factors that differ between exposed and unexposed children. We developed a novel rat model of perinatal fentanyl exposure to characterize NOWS symptoms and investigate enduring behavioral and molecular outcomes. Offspring born to fentanyl-exposed dams exhibited reduced survival, lower body weight, spontaneous withdrawal symptoms, and mechanical hypersensitivity. In adolescence, these rats displayed negative affect, while in adulthood, they showed increased fentanyl self-administration, heightened drug-seeking during reinstatement, and elevated corticosterone levels during withdrawal. To explore the molecular underpinnings of these physiological and behavioral outcomes, we conducted RNA-seq in the central amygdala of adult rats, revealing dysregulated pathways related to GPCR signaling, adaptive immune response and neurodevelopmental processes. These transcriptional changes provide insights into the mechanisms driving addiction vulnerability and stress-related behaviors following early fentanyl exposure. Our findings highlight the lasting impact of perinatal opioid exposure in an experimental system that avoids many of the confounds that plague studies in humans, underscoring the need for preclinical models to study NOWS and its long-term consequences. This model offers translational relevance for developing therapeutic strategies to mitigate NOWS and reduce neuropsychiatric risks associated with prenatal opioid exposure.<\/jats:p>","DOI":"10.1101\/2025.05.20.655167","type":"posted-content","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T17:05:46Z","timestamp":1747847146000},"source":"Crossref","is-referenced-by-count":0,"title":["Perinatal Fentanyl Exposure Drives Enduring Addiction Risk and Central Amygdala Gene Dysregulation"],"prefix":"10.64898","author":[{"given":"Courtney P.","family":"Wood","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeji","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria G.","family":"Balaguer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Campo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selen","family":"Dirik","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan A.","family":"Montoya","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M. R.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle M.","family":"Palermo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parsa K.","family":"Naghshineh","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara R. M. U.","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham A.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"},{"name":"Institute for Genomic Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Telese","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4782-7430","authenticated-orcid":false,"given":"Giordano","family":"de Guglielmo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041123212646000_2025.05.20.655167v2.1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12895"},{"key":"2026041123212646000_2025.05.20.655167v2.2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2470-20.2020"},{"key":"2026041123212646000_2025.05.20.655167v2.3","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"2026041123212646000_2025.05.20.655167v2.4","doi-asserted-by":"publisher","DOI":"10.1177\/0009922814549545"},{"key":"2026041123212646000_2025.05.20.655167v2.5","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"2026041123212646000_2025.05.20.655167v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07440-x"},{"key":"2026041123212646000_2025.05.20.655167v2.7","doi-asserted-by":"crossref","unstructured":"Conradt, E. , Flannery, T. , Aschner, J. L. , Annett, R. D. , Croen, L. A. , Duarte, C. S. , Friedman, A. M. , Guille, C. , Hedderson, M. M. , Hofheimer, J. A. , Jones, M. R. , Ladd-Acosta, C. , McGrath, M. , Moreland, A. , Neiderhiser, J. M. , Nguyen, R. H. N. , Posner, J. , Ross, J. L. , Savitz, D. A. , Ondersma, S. J. , Lester, B. M. , 2019. Prenatal Opioid Exposure: Neurodevelopmental Consequences and Future Research Priorities. Pediatrics 144.","DOI":"10.1542\/peds.2019-0128"},{"key":"2026041123212646000_2025.05.20.655167v2.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2006.12.001"},{"key":"2026041123212646000_2025.05.20.655167v2.9","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301557"},{"key":"2026041123212646000_2025.05.20.655167v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphysparis.2010.08.007"},{"key":"2026041123212646000_2025.05.20.655167v2.11","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-016-4452-1"},{"key":"2026041123212646000_2025.05.20.655167v2.12","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12851"},{"key":"2026041123212646000_2025.05.20.655167v2.13","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2019.00292"},{"key":"2026041123212646000_2025.05.20.655167v2.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2024.100527"},{"key":"2026041123212646000_2025.05.20.655167v2.15","doi-asserted-by":"publisher","DOI":"10.1007\/BF00433012"},{"key":"2026041123212646000_2025.05.20.655167v2.16","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026041123212646000_2025.05.20.655167v2.17","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2023.1202099"},{"key":"2026041123212646000_2025.05.20.655167v2.18","doi-asserted-by":"publisher","DOI":"10.1017\/S0954579408000576"},{"key":"2026041123212646000_2025.05.20.655167v2.19","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(77)90720-x"},{"key":"2026041123212646000_2025.05.20.655167v2.20","first-page":"126","article-title":"Opioid Use Disorder Documented at Delivery Hospitalization-United States, 1999-2014","volume":"22","year":"2024","journal-title":"Focus (Am Psychiatr Publ)"},{"key":"2026041123212646000_2025.05.20.655167v2.21","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32299"},{"key":"2026041123212646000_2025.05.20.655167v2.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.earlhumdev.2007.01.013"},{"key":"2026041123212646000_2025.05.20.655167v2.23","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu283"},{"key":"2026041123212646000_2025.05.20.655167v2.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1915143117"},{"key":"2026041123212646000_2025.05.20.655167v2.25","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2023-077664"},{"key":"2026041123212646000_2025.05.20.655167v2.26","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6531a2"},{"key":"2026041123212646000_2025.05.20.655167v2.27","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6609a2"},{"key":"2026041123212646000_2025.05.20.655167v2.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2009.03.038"},{"key":"2026041123212646000_2025.05.20.655167v2.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.forsciint.2018.05.042"},{"key":"2026041123212646000_2025.05.20.655167v2.30","doi-asserted-by":"crossref","unstructured":"Laboute, T. , Gandia, J. , Pellissier, L. P. , Corde, Y. , Rebeillard, F. , Gallo, M. , Gauthier, C. , Leaute, A. , Diaz, J. , Poupon, A. , Kieffer, B. L. , Le Merrer, J. , Becker, J. A. , 2020. The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs. Elife 9.","DOI":"10.7554\/eLife.50519"},{"key":"2026041123212646000_2025.05.20.655167v2.31","doi-asserted-by":"publisher","DOI":"10.1055\/a-1877-9291"},{"key":"2026041123212646000_2025.05.20.655167v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-020-01297-2"},{"key":"2026041123212646000_2025.05.20.655167v2.33","first-page":"E116","article-title":"Association study of RGS2 gene polymorphisms with panic disorder in Japanese","volume":"55","year":"2010","journal-title":"Kobe J Med Sci"},{"key":"2026041123212646000_2025.05.20.655167v2.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2024.110060"},{"key":"2026041123212646000_2025.05.20.655167v2.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41588--01016-z"},{"key":"2026041123212646000_2025.05.20.655167v2.36","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4274(02)00505-2"},{"key":"2026041123212646000_2025.05.20.655167v2.37","doi-asserted-by":"publisher","DOI":"10.1017\/S0012162201001219"},{"key":"2026041123212646000_2025.05.20.655167v2.38","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-024-2720-8"},{"key":"2026041123212646000_2025.05.20.655167v2.39","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2012.3951"},{"key":"2026041123212646000_2025.05.20.655167v2.40","doi-asserted-by":"publisher","DOI":"10.1016\/0376-8716(93)90032-L"},{"key":"2026041123212646000_2025.05.20.655167v2.41","first-page":"391","article-title":"Amplitude-integrated EEG in infants with neonatal abstinence syndrome","volume":"12","year":"2019","journal-title":"J Neonatal Perinatal Med"},{"key":"2026041123212646000_2025.05.20.655167v2.42","first-page":"28","article-title":"Mid-Gestational Enlargement of Fetal Thalami in Women Exposed to Methadone during Pregnancy","volume":"1","year":"2014","journal-title":"Front Surg"},{"key":"2026041123212646000_2025.05.20.655167v2.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2025.110372"},{"key":"2026041123212646000_2025.05.20.655167v2.44","doi-asserted-by":"crossref","unstructured":"Simpson, S. , Kimbrough, A. , Boomhower, B. , McLellan, R. , Hughes, M. , Shankar, K. , de Guglielmo, G. , George, O. , 2020. Depletion of the Microbiome Alters the Recruitment of Neuronal Ensembles of Oxycodone Intoxication and Withdrawal. eNeuro 7.","DOI":"10.1523\/ENEURO.0312-19.2020"},{"key":"2026041123212646000_2025.05.20.655167v2.45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"2026041123212646000_2025.05.20.655167v2.46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0107271"},{"key":"2026041123212646000_2025.05.20.655167v2.47","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2016.3750"},{"key":"2026041123212646000_2025.05.20.655167v2.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2019.107625"},{"key":"2026041123212646000_2025.05.20.655167v2.49","first-page":"1","article-title":"Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2010-2014","volume":"65","year":"2016","journal-title":"Natl Vital Stat Rep"},{"key":"2026041123212646000_2025.05.20.655167v2.50","doi-asserted-by":"publisher","DOI":"10.1542\/peds.63.1.135"},{"key":"2026041123212646000_2025.05.20.655167v2.51","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1448750"},{"key":"2026041123212646000_2025.05.20.655167v2.52","doi-asserted-by":"crossref","unstructured":"Yamaguchi, H. , Morikawa, M. , Kikkawa, M. , 2023. Calaxin stabilizes the docking of outer arm dyneins onto ciliary doublet microtubule in vertebrates. Elife 12.","DOI":"10.7554\/eLife.84860"},{"key":"2026041123212646000_2025.05.20.655167v2.53","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.8b00572"},{"key":"2026041123212646000_2025.05.20.655167v2.54","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.1039055"},{"key":"2026041123212646000_2025.05.20.655167v2.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2017.08.031"},{"key":"2026041123212646000_2025.05.20.655167v2.56","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"2026041123212646000_2025.05.20.655167v2.57","doi-asserted-by":"publisher","DOI":"10.1038\/jp.2014.111"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.05.20.655167","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:12:49Z","timestamp":1782277969000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.05.20.655167"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,21]]},"references-count":57,"URL":"https:\/\/doi.org\/10.1101\/2025.05.20.655167","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.neuropharm.2025.110581","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,5,21]]},"subtype":"preprint"}}