{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:07:04Z","timestamp":1793196424853,"version":"4.5.0"},"reference-count":89,"publisher":"National Academy of Sciences","issue":"6","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["W1232"],"award-info":[{"award-number":["W1232"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P 33955-B"],"award-info":[{"award-number":["P 33955-B"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P 32017"],"award-info":[{"award-number":["P 32017"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,2,7]]},"abstract":"<jats:p>\n                    Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in\u00a0vitro do not fully correlate to their pharmacological profile in\u00a0vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, \u03b1-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in\u00a0vitro, computational, and in\u00a0vivo approaches. We found that in\u00a0vitro drug-binding kinetics at DAT correlate with the time-course of in\u00a0vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow\n                    <jats:italic>\n                      k\n                      <jats:sub>off<\/jats:sub>\n                    <\/jats:italic>\n                    ) of\n                    <jats:italic>S<\/jats:italic>\n                    -enantiomers of pyrovalerone analogs from DAT predicts their more persistent in\u00a0vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in\u00a0vivo profile of effects produced by psychostimulant drugs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2114204120","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T13:38:40Z","timestamp":1675345120000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":24,"title":["Persistent binding at dopamine transporters determines sustained psychostimulant effects"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0518-5791","authenticated-orcid":false,"given":"Marco","family":"Niello","sequence":"first","affiliation":[{"name":"Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna, 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Schindler Stereoselective neurochemical behavioral and cardiovascular effects of \u03b1-pyrrolidinovalerophenone enantiomers in male rats. Addict. 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