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These treatments may suffer from the development of tolerance and opioid receptor supersensitivity, as suggested by preclinical models showing activation of these processes during and after subchronic high\u2010dose administration of the short\u2010acting opioid antagonist naloxone. In the present study, we compared equipotent low and moderate daily doses of naltrexone and nalmefene, two opioid antagonists in the clinical practice for treatment of alcoholism. The antagonists were given here subcutaneously for 7\u2009days either as daily injections or continuous osmotic minipump\u2010driven infusions to alcohol\u2010preferring AA rats having trained to drink 10% alcohol in a limited access protocol. One day after stopping the antagonist treatment, [<jats:sup>35<\/jats:sup>S]GTP\u03b3S autoradiography on brain cryostat sections was carried out to examine the coupling of receptors to G protein activation. The results prove the efficacy of repeated injections over infused opioid antagonists in reducing alcohol drinking. Tolerance to the reducing effect on alcohol drinking and to the enhancement of G protein coupling to \u03bc\u2010opioid receptors in various brain regions were consistently detected only after infused antagonists. Supersensitivity of \u03ba\u2010opioid receptors was seen in the ventral and dorsal striatal regions especially by infused nalmefene. Nalmefene showed no clear agonistic activity in rat brain sections or at human recombinant \u03ba\u2010opioid receptors. The findings support the as\u2010needed dosing practice, rather than the standard continual dosing, in the treatment of alcoholism with opioid receptor antagonists.<\/jats:p>","DOI":"10.1111\/adb.12393","type":"journal-article","created":{"date-parts":[[2016,3,19]],"date-time":"2016-03-19T00:50:31Z","timestamp":1458348631000},"page":"1022-1035","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0683-4009","authenticated-orcid":false,"given":"Esa R.","family":"Korpi","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine University of Helsinki Finland"},{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore 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