{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:33:56Z","timestamp":1791599636271,"version":"4.3.4"},"reference-count":65,"publisher":"Society for Neuroscience","issue":"4","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DA063220"],"award-info":[{"award-number":["DA063220"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DA054900"],"award-info":[{"award-number":["DA054900"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"HHS | National Institutes of Health","award":["DA058613"],"award-info":[{"award-number":["DA058613"]}]}],"content-domain":{"domain":["eneuro.org"],"crossmark-restriction":true},"short-container-title":["eNeuro"],"accepted":{"date-parts":[[2026,3,10]]},"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:p>Environmental enrichment (EE) reduces vulnerability to multiple drugs of abuse, yet its impact on fentanyl use and relapse-like behavior remains unclear. Here, we tested whether long-term, nonsocial, object-based EE alters fentanyl self-administration, extinction, and stress-induced reinstatement in male and female rats. Rats were individually housed in either standard nonenriched (NE) conditions or in EE cages containing a rotating set of novel objects beginning at least 3\u2005d prior to self-administration. EE did not impact acquisition of fentanyl self-administration but reduced fentanyl intake during maintenance of self-administration and reduced the persistence of drug-seeking in extinction. Following extinction, yohimbine robustly reinstated drug-seeking behavior in NE rats but reinstatement in EE rats was markedly attenuated, indicating reduced sensitivity to stress-induced relapse triggers. Circulating corticosterone levels were lower in EE rats across the experiment and were positively correlated with reinstatement responding, suggesting that enrichment's protective effects may be mediated in part by reduced hypothalamic-pituitary-adrenal (HPA) axis activation. These findings demonstrate that object-based EE, even in the absence of social enrichment, is sufficient to blunt fentanyl use, facilitate extinction, and constrain stress-induced reinstatement. The results highlight the role of environmental context and stress regulation in fentanyl vulnerability and suggest that enrichment-inspired, nonsocial interventions may offer a scalable strategy to reduce opioid use and relapse risk.<\/jats:p>","DOI":"10.1523\/eneuro.0447-25.2026","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T17:50:18Z","timestamp":1776102618000},"page":"ENEURO.0447-25.2026","update-policy":"https:\/\/doi.org\/10.1523\/eneuro.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Environmental Enrichment Attenuates Fentanyl-Seeking Behavior and Protects against Stress-Induced Reinstatement in Both Male and Female Rats"],"prefix":"10.1523","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7360-8971","authenticated-orcid":false,"given":"Jessica A.","family":"Higginbotham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna J.","family":"Dearman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateo","family":"Pujol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Teich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan","family":"Maqbool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose A.","family":"Moron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.1","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1097\/FBP.0b013e3283584765","article-title":"Environmental enrichment during development decreases intravenous self-administration of methylphenidate at low unit doses in rats","volume":"23","author":"Alvers","year":"2012","journal-title":"Behav Pharmacol"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2010.04.005"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2009.11.030"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.4","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.011163"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2003.09.005"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03587.x"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.7","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-013-3120-y"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2006.01.005"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.beproc.2006.08.007"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.10","unstructured":"CDC\/NCHS (2019) National vital statistics system, mortality, CDC WONDER . Atlanta, GA: Us Department of Health and Human Services, CDC."},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.11","doi-asserted-by":"crossref","first-page":"e141","DOI":"10.15190\/d.2021.20","article-title":"Substance use during COVID-19 pandemic: impact on the underserved communities","volume":"9","author":"Chacon","year":"2021","journal-title":"Discoveries (Craiova)"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.12","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2009.127"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.13","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1093\/scan\/nsab029","article-title":"The role of social isolation in opioid addiction","volume":"16","author":"Christie","year":"2021","journal-title":"Soc Cogn Affect Neurosci"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.14","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2008.0090"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.15","doi-asserted-by":"crossref","first-page":"e217112","DOI":"10.1001\/jamanetworkopen.2021.7112","article-title":"Trends in drug overdose mortality in Ohio during the first 7 months of the COVID-19 pandemic","volume":"4","author":"Currie","year":"2021","journal-title":"JAMA Netw Open"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.16","doi-asserted-by":"crossref","first-page":"564184","DOI":"10.3389\/fnbeh.2020.564184","article-title":"Environmental enrichment as a strategy to confront social isolation under the COVID-19 pandemic","volume":"14","author":"Davim","year":"2021","journal-title":"Front Behav Neurosci"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.17","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-006-0565-8"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.18","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-14-05529.1998"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.19","doi-asserted-by":"publisher","DOI":"10.1177\/2049463720973703"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.20","doi-asserted-by":"crossref","first-page":"1380051","DOI":"10.3389\/forgp.2024.1380051","article-title":"The hidden costs of working from home: examining loneliness, role overload, and the role of social support during and beyond the COVID-19 lockdown","volume":"2","author":"Fostervold","year":"2024","journal-title":"Front Organ Psychol"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/BF02246959","article-title":"In a drug discrimination procedure isolation-reared rats generalize to lower doses of cocaine and amphetamine than rats reared in an enriched environment","volume":"110","author":"Fowler","year":"1993","journal-title":"Psychopharmacology"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2019.172829"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.23","doi-asserted-by":"crossref","unstructured":"Garnett M , Mini\u00f1o A (2024) Drug overdose deaths in the United States, 2003\u20132023 . NCHS Data Brief, no 522. Hyattsville, MD: National Center for Health Statistics.10.15620\/cdc\/170565","DOI":"10.15620\/cdc\/170565"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.24","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1007\/s11524-022-00610-0","article-title":"Impact of the COVID-19 pandemic on opioid overdose deaths: a spatiotemporal analysis","volume":"99","author":"Ghose","year":"2022","journal-title":"J Urban Health"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.25","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-010-2060-z"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.26","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12758"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.27","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-002-1134-y"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.28","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-012-2868-9"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.29","doi-asserted-by":"crossref","first-page":"100684","DOI":"10.1016\/j.ynstr.2024.100684","article-title":"Basal cortisol level modulates stress-induced opioid-seeking behavior","volume":"33","author":"Greenwald","year":"2024","journal-title":"Neurobiol Stress"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.30","doi-asserted-by":"publisher","DOI":"10.1097\/FBP.0b013e32831c3b18"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-020-00919-x"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.32","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.neuron.2025.02.013","article-title":"Estradiol protects against pain-facilitated fentanyl use via suppression of opioid-evoked dopamine activity in males","volume":"113","author":"Higginbotham","year":"2025","journal-title":"Neuron"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.33","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-017-4734-2"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.34","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2000.7415"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.06.037"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.36","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.160.4.687"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.37","doi-asserted-by":"publisher","DOI":"10.1151\/spp021113"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.38","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhu119"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.39","doi-asserted-by":"crossref","first-page":"173471","DOI":"10.1016\/j.pbb.2022.173471","article-title":"Neurobehavioral effects of environmental enrichment and drug abuse vulnerability: an updated review","volume":"221","author":"Malone","year":"2022","journal-title":"Pharmacol Biochem Behav"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.40","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s40122-021-00243-2","article-title":"COVID-19 and the opioid epidemic: two public health emergencies that intersect with chronic pain","volume":"10","author":"Manchikanti","year":"2021","journal-title":"Pain Ther"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.41","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2010.86"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.42","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2015.142"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.43","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/s41386-024-01828-z","article-title":"A locus ceruleus to dorsal hippocampus pathway mediates cue-induced reinstatement of opioid self-administration in male and female rats","volume":"49","author":"Markovic","year":"2024","journal-title":"Neuropsychopharmacology"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.44","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7006a4"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.45","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-017-4536-6"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.46","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.devbrainres.2004.09.001","article-title":"Effects of environmental enrichment on behavior and dopamine transporter function in medial prefrontal cortex in adult rats prenatally treated with cocaine","volume":"153","author":"Neugebauer","year":"2004","journal-title":"Dev Brain Res"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.47","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1970"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.48","doi-asserted-by":"crossref","first-page":"28","DOI":"10.36923\/jicc.v23i3.122","article-title":"Environmental impact on relapse and motivation recovery among drug addicts","volume":"23","author":"Razali","year":"2023","journal-title":"J Intercult Commun"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.49","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1080\/0968763031000077733","article-title":"Risk factors associated with drug use: the importance of \u2018risk environment\u2019","volume":"10","author":"Rhodes","year":"2003","journal-title":"Drugs Educ Prev Policy"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.50","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3389\/fnbeh.2018.00177","article-title":"Environmental enrichment during adolescence acts as a protective and therapeutic tool for ethanol binge-drinking, anxiety-like, novelty seeking and compulsive-like behaviors in C57BL\/6J mice during adulthood","volume":"12","author":"Rodr\u00edguez-Ortega","year":"2018","journal-title":"Front Behav Neurosci"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.51","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-010-0447-y"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.52","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-002-1224-x"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2004.02.032"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.54","doi-asserted-by":"publisher","DOI":"10.1007\/s11920-007-0050-6"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.55","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2008.51"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2010.08.002"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2020.09.001"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2009.01.016"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.59","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyv092"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.60","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.neuropharm.2017.05.022","article-title":"Role of glucocorticoid receptor-mediated mechanisms in cocaine memory enhancement","volume":"123","author":"Stringfield","year":"2017","journal-title":"Neuropharmacology"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.61","doi-asserted-by":"publisher","DOI":"10.1017\/S1461145709990472"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.62","doi-asserted-by":"publisher","DOI":"10.1111\/j.1369-1600.2011.00358.x"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.63","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1007\/s00213-020-05749-9","article-title":"Effects of kappa opioid receptor agonists on fentanyl versus food choice in male and female rats: contingent versus non-contingent administration","volume":"238","author":"Townsend","year":"2021","journal-title":"Psychopharmacology"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.64","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.3109\/10826089109071032","article-title":"Environmental influences on relapse in substance use disorders","volume":"25","author":"Tucker","year":"1991","journal-title":"Int J Addict"},{"key":"2026042010500895000_13.4.ENEURO.0447-25.2026.65","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21907"}],"container-title":["eneuro"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/ENEURO.0447-25.2026","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/ENEURO.0447-25.2026","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T17:50:22Z","timestamp":1776707422000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.eneuro.org\/lookup\/doi\/10.1523\/ENEURO.0447-25.2026"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":65,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,20]]},"published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1523\/ENEURO.0447-25.2026"],"URL":"https:\/\/doi.org\/10.1523\/eneuro.0447-25.2026","relation":{},"ISSN":["2373-2822"],"issn-type":[{"value":"2373-2822","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]}}}