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Cocaine self\u2010administration with the intermittent access (IntA) procedure produces a robust addiction\u2010like state that is orexin\u2010dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self\u2010administration of fentanyl. Different groups of male rats were either given continuous access in 1\u2010h period (short access [ShA]), 6\u2010h period (long access [LgA]), or IntA (5 min of access separated by 25 min of no access for 6 h) to fentanyl for 14 days. IntA produced a greater escalation of fentanyl intake, increased motivation for fentanyl on a behavioral economics task, persistent drug seeking during abstinence, and stronger cue\u2010induced reinstatement compared with rats given ShA or LgA. We found that addiction behaviors induced by IntA to fentanyl were reversed by the orexin\u20101 receptor antagonist SB\u2010334867. IntA to fentanyl was also associated with a persistent increase in the number of orexin neurons. Together, these results indicate that the IntA model is a useful tool in the study of opioid addiction and that the orexin system is critical for the maintenance of addiction behaviors induced by IntA self\u2010administration of fentanyl.<\/jats:p>","DOI":"10.1111\/adb.12946","type":"journal-article","created":{"date-parts":[[2020,8,15]],"date-time":"2020-08-15T03:41:20Z","timestamp":1597462880000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Intermittent self\u2010administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9074-4879","authenticated-orcid":false,"given":"Jennifer E.","family":"Fragale","sequence":"first","affiliation":[{"name":"Brain Health Institute Rutgers University and Rutgers Biomedical and Health Sciences  Piscataway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9298-8607","authenticated-orcid":false,"given":"Morgan H.","family":"James","sequence":"additional","affiliation":[{"name":"Brain Health Institute Rutgers University and Rutgers Biomedical and Health Sciences  Piscataway New Jersey USA"},{"name":"Florey Institute of Neuroscience and Mental Health University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5034-3816","authenticated-orcid":false,"given":"Gary","family":"Aston\u2010Jones","sequence":"additional","affiliation":[{"name":"Brain Health Institute Rutgers University and Rutgers Biomedical and Health Sciences  Piscataway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,14]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.1.322"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80949-6"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.13170"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12795"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706789"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2018.07.022"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aao4953"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.107906"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12866"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-019-0420-x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.alcohol.2009.07.002"},{"key":"e_1_2_9_13_1","first-page":"34","article-title":"Orexin\/hypocretin\u20101 receptor antagonism reduces ethanol self\u2010administration and reinstatement selectively in highly\u2010motivated rats","volume":"2017","author":"Moorman DE","year":"1654","journal-title":"Brain Res"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12323"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2012.08013.x"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2009.06844.x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0255-19.2019"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.14166"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2016.06.010"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2015.06.012"},{"key":"e_1_2_9_21_1","unstructured":"BeveridgeTJR WP BrewerA ShapiroB MahoneyJJ NewtonTF.Analyzing human cocaine use patterns to inform animal addiction model development. 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