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Here we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DUIs, as measured via voltammetry procedures. While both classes of DUIs reduced DA clearance rate, an effect significantly related to their DAT affinity, only typical DUIs elicited a significant stimulation of evoked DA release, an effect unrelated to their DAT affinity, which suggests a mechanism of action other than or in addition to DAT blockade. When given in combination, typical DUIs enhance the stimulatory effects of cocaine on evoked DA release while atypical DUIs blunt them. Pretreatments with an inhibitor of CaMKII\u03b1, a kinase that interacts with DAT and that regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted the effects of cocaine on evoked DA release. Our results suggest a role for CaMKII\u03b1 in modulating the effects of cocaine on evoked DA release without affecting cocaine inhibition of DA reuptake. This effect is related to a specific DAT conformation stabilized by cocaine. Moreover, atypical DUIs, which prefer a distinct DAT conformation, blunt cocaine\u2019s neurochemical and behavioral effects, indicating a unique mechanism underlying their potential as medications for treating psychostimulant use disorder.<\/jats:p>","DOI":"10.1038\/s41398-023-02493-4","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T13:02:33Z","timestamp":1686661353000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release"],"prefix":"10.1038","volume":"13","author":[{"given":"Jacqueline D.","family":"Keighron","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4745-0151","authenticated-orcid":false,"given":"Jordi","family":"Bonaventura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8928-0130","authenticated-orcid":false,"given":"Jae-Won","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily M.","family":"DeMarco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melinda","family":"Hersey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianjing","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"Sandtner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0398-4917","authenticated-orcid":false,"given":"Michael","family":"Michaelides","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1339-7444","authenticated-orcid":false,"given":"Harald H.","family":"Sitte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4812-9474","authenticated-orcid":false,"given":"Amy Hauck","family":"Newman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9526-9878","authenticated-orcid":false,"given":"Gianluigi","family":"Tanda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,6,13]]},"reference":[{"key":"2493_CR1","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1146\/annurev.pharmtox.47.120505.105140","volume":"47","author":"AE Fleckenstein","year":"2007","unstructured":"Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR. 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