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Both alcohol and nicotine can activate opioid systems in reward\u2010related brain regions, leading to adaptive changes in opioid signalling upon chronic exposure. The potential role of these adaptations for comorbidity is presently unknown. Here, we examined the contribution of \u03bc and \u03ba\u2010opioid receptors to nicotine\u2010induced escalation of alcohol self\u2010administration in rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Chronic nicotine was tested on alcohol self\u2010administration and motivation to obtain alcohol. We then tested the effect of the \u03ba antagonist CERC\u2010501 and the preferential \u03bc receptor antagonist naltrexone on basal and nicotine\u2010escalated alcohol self\u2010administration. To probe \u03bc or \u03ba receptor adaptations, receptor binding and G\u2010protein coupling assays were performed in reward\u2010related brain regions. Finally, dopaminergic activity in response to alcohol was examined, using phosphorylation of DARPP\u201032 in nucleus accumbens as a biomarker.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Nicotine robustly induced escalation of alcohol self\u2010administration and motivation to obtain alcohol. This was blocked by naltrexone but not by CERC\u2010501. Escalation of alcohol self\u2010administration was associated with decreased DAMGO\u2010stimulated \u03bc receptor signalling in the ventral tegmental area (VTA) and decreased pDARPP\u201032 in the nucleus accumbens shell in response to alcohol.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Collectively, these results suggest that nicotine contributes to escalate alcohol self\u2010administration through a dysregulation of \u03bc receptor activity in the VTA. These data imply that targeting \u03bc rather than \u03ba receptors may be the preferred pharmacotherapeutic approach for the treatment of alcohol use disorder when nicotine use contributes to alcohol consumption.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15210","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T15:55:04Z","timestamp":1595433304000},"page":"4516-4531","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Nicotine increases alcohol self\u2010administration in male rats via a \u03bc\u2010opioid mechanism within the mesolimbic pathway"],"prefix":"10.1111","volume":"177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5726-4814","authenticated-orcid":false,"given":"Esi","family":"Domi","sequence":"first","affiliation":[{"name":"Center for Social and Affective Neuroscience, BKV Link\u00f6ping University  Link\u00f6ping S\u2010581 85 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