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In this study, we first examined the dose dependence of cocaine\u2010induced DAT trafficking and hyperactivity in rats, demonstrating that cocaine at an intraperitoneal dose of 10\u00a0mg\/kg or higher led to redistribution of most DAT to the plasma membrane while inducing significant hyperactivity in rats. However, administration of 5\u2010mg\/kg cocaine (ip) did not significantly induce DAT trafficking or hyperactivity in rats. So the threshold (intraperitoneal) dose of cocaine that can significantly induce DAT trafficking or hyperactivity should be between 5 and 10\u00a0mg\/kg. These data suggest that when a cocaine dose is high enough to induce significant hyperactivity, it can also significantly induce DAT trafficking to the plasma membrane. Further, the threshold brain cocaine concentration required to induce significant hyperactivity and DAT trafficking was estimated to be ~2.0\u2009\u00b1\u20090.8\u00a0\u03bcg\/g. Particularly, for treatment of cocaine abuse, previous studies demonstrated that an exogenous cocaine\u2010metabolizing enzyme, for example, CocH3\u2010Fc(M3), can effectively block cocaine\u2010induced hyperactivity. However, it was unknown whether an enzyme could also effectively block cocaine\u2010induced DAT trafficking to the plasma membrane. This study demonstrates, for the first time, that the enzyme is also capable of effectively blocking cocaine from reaching the brain even with a lethal dose of 60\u2010mg\/kg cocaine (ip) and, thus, powerfully preventing cocaine\u2010induced physiological effects such as the hyperactivity and DAT trafficking.<\/jats:p>","DOI":"10.1111\/adb.13089","type":"journal-article","created":{"date-parts":[[2021,8,7]],"date-time":"2021-08-07T05:25:19Z","timestamp":1628313919000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cocaine hydrolase blocks cocaine\u2010induced dopamine transporter trafficking to the plasma membrane"],"prefix":"10.1111","volume":"27","author":[{"given":"Jing","family":"Deng","sequence":"first","affiliation":[{"name":"Molecular Modeling and Biopharmaceutical Center  Lexington Kentucky USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy University of Kentucky  Lexington Kentucky 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