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In this study, we examined the effects of intermittent\u2010 and continuous\u2010access self\u2010administration on heroin intake, patterns of self\u2010administration and cue\u2010induced heroin\u2010seeking, after forced or voluntary abstinence, in male and female rats. We also modelled brain levels of heroin and its active metabolites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Rats were trained to self\u2010administer a palatable solution and then heroin (0.075\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup> per inf) either continuously (6\u2009h\u00b7day<jats:sup>\u22121<\/jats:sup>; 10\u2009days) or intermittently (6\u2009h\u00b7day<jats:sup>\u22121<\/jats:sup>; 5\u2010min access every 30\u2010min; 10\u2009days). Brain levels of heroin and its metabolites were modelled using a pharmacokinetic software. Next, heroin\u2010seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The oestrous cycle was measured using a vaginal smear test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Intermittent access exacerbated heroin self\u2010administration and was characterized by a burst\u2010like intake, yielding higher brain peaks of heroin and 6\u2010monoacetylmorphine concentrations. Moreover, intermittent access increased cue\u2010induced heroin\u2010seeking during early, but not late abstinence. Heroin\u2010seeking was higher in females after intermittent, but not continuous access, and this effect was independent of the oestrous cycle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Intermittent heroin access in rats resembles critical features of heroin use disorder: a self\u2010administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v180.7\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v180.7\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15791","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T22:52:47Z","timestamp":1641423167000},"page":"910-926","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Increased heroin intake and relapse vulnerability in intermittent relative to continuous self\u2010administration: Sex differences in rats"],"prefix":"10.1111","volume":"180","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0475-6641","authenticated-orcid":false,"given":"Ginevra","family":"D'Ottavio","sequence":"first","affiliation":[{"name":"Laboratory affiliated to Institute Pasteur Italia \u2013 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