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Compelling evidence indicates that mixed opioid receptor agonists, particularly bifunctional compounds that target nociceptin\/orphanin FQ peptide (NOP) and mu opioid receptors, may be useful for the treatment of cocaine addiction. Here, we verify that potent and selective pharmacological activation of NOP receptors is sufficient to reduce relevant facets of cocaine addiction in animal models. Accordingly, we determined whether systemic injections of the small molecule AT\u2010312 (0, 1, 3 mg\/kg) could reduce operant cocaine self\u2010administration, motivation for cocaine, and vulnerability to cocaine relapse in rats. Results indicate that a potent and selective NOP receptor agonist was equally efficacious in reducing the number of cocaine infusions in short (1\u2010hour), as well as long (6\u2010hour) access sessions. When tested on an economic\u2010demand reinforcement schedule, AT\u2010312 reduced Q<jats:sub>0<\/jats:sub>, the parameter that describes the amount of drug consumed at zero price, while leaving the parameter \u03b1, a measure of motivation for drug consumption, unaltered. Furthermore, AT\u2010312 successfully reduced conditioned reinstatement of cocaine seeking. In contrast, the NOP receptor agonist did not modify food self\u2010administration. Blockade of the NOP receptor with the antagonist SB\u2010612111 prevented the effect of AT\u2010312 in decreasing cocaine\u2010reinforced responding under a 2\u2010hour fixed ratio 1 schedule, suggesting a NOP receptor\u2010mediated mechanism. This work demonstrates that potent and selective activation of NOP receptors is sufficient to decrease cocaine taking and seeking behaviors in rats.<\/jats:p>","DOI":"10.1111\/adb.12844","type":"journal-article","created":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T05:59:04Z","timestamp":1573451944000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Potent and selective NOP receptor activation reduces cocaine self\u2010administration in rats by lowering hedonic set point"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8151-0579","authenticated-orcid":false,"given":"Andrea","family":"Cippitelli","sequence":"first","affiliation":[{"name":"Biomedical Science Department Charles E. 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Schmidt College of Medicine Florida Atlantic University  Boca Raton FL United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,11,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/add.12628"},{"issue":"1476","key":"e_1_2_8_3_1","first-page":"2010","article-title":"Announcements: Release of Issue Brief: Unintentional Drug Poisoning in the United States (Reprinted from MMWR, vol 59, pg 300, 2010)","volume":"303","author":"CDC. Centers for Disease Control and Preventions","year":"2010","journal-title":"Jama\u2010J Am Med Assoc"},{"key":"e_1_2_8_4_1","unstructured":"Office of National Drug Control Policy. 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