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Atypical dopamine (DA) transporter (DAT) inhibitors display low addictive liability by themselves and may have therapeutic potential for treatment of psychostimulant use disorders. Here, we report that RDS-04-010, a novel atypical DAT inhibitor that binds to an inward-facing conformation of DAT due to its sulfoxide moiety, displayed distinct pharmacological profiles in animal models of addiction from its sulfide analog, RDS-03-094, a DAT inhibitor that binds to a more outward-facing conformation. Systemic administration of RDS-04-010 dose-dependently inhibited cocaine self-administration, shifted the cocaine self-administration dose-response curve downward, decreased motivation for cocaine seeking under progressive-ratio reinforcement conditions, and inhibited cocaine-primed reinstatement of drug-seeking behavior. RDS-04-010 alone neither altered optical brain-stimulation reward nor evoked reinstatement of drug-seeking behavior. RDS-04-010 substitution for cocaine was not able to maintain self-administration in rats trained to self-administer cocaine. In contrast, RDS-03-094 displayed more cocaine-like reinforcing effects. Its pretreatment upward-shifted both the cocaine self-administration dose-response and optical brain-stimulation reward curves. RDS-03-094 alone was able to reinstate extinguished cocaine-seeking behavior and sustain self-administration during a substitution test. Collectively, these findings suggest that RDS-04-010 is a novel atypical DAT inhibitor with favorable therapeutic potential in reducing cocaine-taking and -seeking behavior with low addictive liability. Moreover, this extensive behavioral evaluation further confirms the role that DAT binding conformation plays in the distinctive profiles of atypical DAT inhibitors that prefer the inward facing conformation.<\/jats:p>","DOI":"10.1038\/s41398-025-03391-7","type":"journal-article","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T16:44:18Z","timestamp":1748105058000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["RDS-04-010: a novel atypical DAT inhibitor that inhibits cocaine taking and seeking and itself has low abuse potential in experimental animals"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5897-4156","authenticated-orcid":false,"given":"Omar","family":"Soler-Cedeno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7180-4378","authenticated-orcid":false,"given":"Ewa","family":"Galaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjing","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Hua","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4812-9474","authenticated-orcid":false,"given":"Amy Hauck","family":"Newman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6482-8104","authenticated-orcid":false,"given":"Zheng-Xiong","family":"Xi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,24]]},"reference":[{"key":"3391_CR1","unstructured":"SAMHSA. 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