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Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3\u00a0weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14\u00a0days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5\u201310.0\u00a0ng\/site), MSX-3 (A2AR antagonist, 5.0\u201320.0\u00a0\u03bcg\/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75\u20133.0\u00a0\u03bcg\/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (\u2265\u20095.0\u00a0ng\/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75\u20133.0\u00a0\u03bcg\/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0\u201320.0\u00a0\u03bcg\/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.<\/jats:p>","DOI":"10.1007\/s11064-021-03238-9","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T12:24:19Z","timestamp":1613996659000},"page":"1081-1091","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The Adenosine A2A Receptor Activation in Nucleus Accumbens Suppress Cue-Induced Reinstatement of Propofol Self-administration in Rats"],"prefix":"10.1007","volume":"46","author":[{"given":"Zhanglei","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingwu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchen","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangfan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingquan","family":"Lian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7953-0992","authenticated-orcid":false,"given":"Binbin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"key":"3238_CR1","doi-asserted-by":"publisher","first-page":"985","DOI":"10.3389\/fphar.2017.00985","volume":"8","author":"CCA Ballerstero-Y\u00e1\u00f1ez","year":"2018","unstructured":"Ballerstero-Y\u00e1\u00f1ez CCA, Merighi S, Gessi S (2018) The role of adenosine receptors in psychostimulant addiction. 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