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We here hypothesize that adolescent exposure to cocaine could alter the rewarding properties of the psychostimulant in adulthood. By employing two of the most widely used animal\u2010experimental\u2010preclinical models to investigate drug addiction, we evaluated whether contingent versus non\u2010contingent cocaine self\u2010administration during adolescence modulates its rewarding threshold in adulthood evaluated by conditioned place preference (CPP). Cocaine self\u2010administration during adolescence increases the rewarding threshold in adulthood; CPP for cocaine was observed at the higher (20\u00a0mg\/kg), but not at the lower (10\u00a0mg\/kg), dose employed. Rats exposed to either contingent or non\u2010contingent cocaine during adolescence exhibited the same behavior in the CPP paradigm suggesting that, under our experimental conditions, cocaine rewarding properties are shaped by the psychostimulant itself and not by its motivational effects. From a mechanistic standpoint, the preference for the 20\u00a0mg\/kg cocaine\u2010paired side in a CPP paradigm appears to depend, at least partially, upon the formation of GluA2\u2010lacking Ca<jats:sup>2+<\/jats:sup>\u2010permeable AMPA receptors and the consequent increase of \u03b1CaMKII activity in the NAc, both of which are instead reduced when the 10\u00a0mg\/kg dose was used. In conclusion, contingent or non\u2010contingent cocaine exposure during adolescence desensitizes adult animals to a rewarding dose of cocaine (10\u00a0mg\/kg) elevating the rewarding threshold necessary (20\u00a0mg\/kg) to drive conditioned place preference, an effect that may predispose to higher consumption of cocaine during adulthood.<\/jats:p>","DOI":"10.1111\/adb.13012","type":"journal-article","created":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T02:29:21Z","timestamp":1611887361000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Repeated exposure to cocaine during adolescence enhances the rewarding threshold for cocaine\u2010conditioned place preference in adulthood"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8045-3146","authenticated-orcid":false,"given":"Lucia","family":"Caffino","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences Universit\u00e0 degli Studi di Milano  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-5583","authenticated-orcid":false,"given":"Federico","family":"Moro","sequence":"additional","affiliation":[{"name":"Experimental Psychopharmacology, Department of Neuroscience Mario Negri Institute for Pharmacological Research IRCCS  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8172-1384","authenticated-orcid":false,"given":"Francesca","family":"Mottarlini","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences Universit\u00e0 degli Studi di Milano  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Targa","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences Universit\u00e0 degli Studi di Milano  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7982-291X","authenticated-orcid":false,"given":"Angelo","family":"Di Clemente","sequence":"additional","affiliation":[{"name":"Experimental Psychopharmacology, Department of Neuroscience Mario Negri Institute for Pharmacological Research IRCCS  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Toia","sequence":"additional","affiliation":[{"name":"Experimental Psychopharmacology, Department of Neuroscience Mario Negri Institute for Pharmacological Research IRCCS  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Orr\u00f9","sequence":"additional","affiliation":[{"name":"Parco Scientifico e Tecnologico della Sardegna Institute of Translational Pharmacology (C.N.R.)  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