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In human addicts, however, polydrug use of cocaine and heroin is common. We used a polydrug self\u2010administration relapse model in rats to determine similarities and differences in brain areas activated during cue\u2010induced reinstatement of heroin and cocaine seeking. We trained rats to lever press for cocaine (1.0\u00a0mg\/kg per infusion, 3\u2010hr\/day, 18\u00a0day) or heroin (0.03\u00a0mg\/kg per infusion) on alternating days (9\u00a0day for each drug); drug infusions were paired with either intermittent or continuous light cue. Next, the rats underwent extinction training followed by tests for cue\u2010induced reinstatement where they were exposed to either heroin\u2010 or cocaine\u2010associated cues. We observed cue\u2010selective reinstatement of drug seeking: the heroin cue selectively reinstated heroin seeking and the cocaine cue selectively reinstated cocaine seeking. We used Fos immunohistochemistry to assess cue\u2010induced neuronal activation in different subregions of the medial prefrontal cortex, dorsal striatum, nucleus accumbens, and amygdala. Fos expression results indicated that only the prelimbic cortex (<jats:styled-content style=\"fixed-case\">PL<\/jats:styled-content>) was activated by both heroin and cocaine cues; in contrast, no significant cue\u2010induced neuronal activation was observed in other brain areas. <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> in situ hybridization indicated that the proportion of glutamatergic and <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>ergic markers in <jats:styled-content style=\"fixed-case\">PL<\/jats:styled-content> Fos\u2010expressing cells was similar for the heroin and cocaine cue\u2010activated neurons. Overall, the results indicate that <jats:styled-content style=\"fixed-case\">PL<\/jats:styled-content> may be a common brain area involved in both heroin and cocaine seeking during polydrug use.<\/jats:p>","DOI":"10.1111\/ejn.14203","type":"journal-article","created":{"date-parts":[[2018,10,11]],"date-time":"2018-10-11T14:02:26Z","timestamp":1539266546000},"page":"165-178","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Prelimbic cortex is a common brain area activated during cue\u2010induced reinstatement of cocaine and heroin seeking in a polydrug self\u2010administration rat model"],"prefix":"10.1111","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5480-0474","authenticated-orcid":false,"given":"Francisco J.","family":"Rubio","sequence":"first","affiliation":[{"name":"Neuronal Ensembles in Addiction Section Behavioral Neuroscience Research Branch National Institute on Drug Abuse Intramural Research Program National Institutes of Health  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5835-4683","authenticated-orcid":false,"given":"Richard","family":"Quintana\u2010Feliciano","sequence":"additional","affiliation":[{"name":"Neuronal Ensembles in Addiction Section Behavioral Neuroscience Research Branch National Institute on Drug Abuse Intramural Research Program National Institutes of Health  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon L.","family":"Warren","sequence":"additional","affiliation":[{"name":"Neuronal Ensembles in Addiction Section Behavioral Neuroscience Research Branch National Institute on Drug Abuse Intramural Research Program National Institutes of Health  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Li","sequence":"additional","affiliation":[{"name":"Neurobiology of Relapse Section Behavioral Neuroscience Research Branch National Institute on Drug Abuse Intramural Research Program National Institutes of Health  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailyn F. 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