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Depending on cocaine amount in\u2010taken, one\u2010time exposure in rats could lead to most (&gt;95% of total) of DAT translocating to plasma membrane of the dopaminergic neurons compared to normal DAT distribution (~5.7% on the plasma membrane). Without further cocaine exposure, the time course of striatal DAT distribution, in terms of intracellular and plasma membrane fractions of DAT, represents a recovery process of the dopaminergic system. In this study, we demonstrated that after an acute cocaine exposure of 20\u2009mg\/kg (i.p.), the initial recovery process from days 1 to 15 in rats was relatively faster (from &gt;95% on day 1 to ~35.4% on day 15). However, complete recovery of the striatal DAT distribution may take about 60\u2009days. In another situation, with repeated cocaine exposures for once every other day for a total of 17 doses of 20\u2009mg\/kg cocaine (i.p.) from days 0 to 32, the complete recovery of striatal DAT distribution may take an even longer time (about 90\u2009days), which represents a consequence of chronic cocaine use. Further, we demonstrated that a highly efficient Fc\u2010fused cocaine hydrolase, CocH5\u2010Fc(M6), effectively blocked cocaine\u2010induced hyperactivity and DAT trafficking with repeated cocaine exposures by maintaining a plasma CocH5\u2010Fc(M6) concentration \u226558.7\u00a0\u00b1\u00a02.9\u00a0nM in rats. The cocaine hydrolase protected dopaminergic system and helped the cocaine\u2010altered DAT distribution to recover by preventing the dopaminergic system from further damage by cocaine.<\/jats:p>","DOI":"10.1111\/adb.13179","type":"journal-article","created":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T08:10:31Z","timestamp":1652256631000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Recovery of dopaminergic system after cocaine exposure and impact of a long\u2010acting cocaine hydrolase"],"prefix":"10.1111","volume":"27","author":[{"given":"Jing","family":"Deng","sequence":"first","affiliation":[{"name":"Molecular Modeling and Biopharmaceutical Center University of Kentucky 789 South Limestone Street Lexington Kentucky 40536 USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy University of Kentucky 789 South Limestone Street Lexington Kentucky 40536 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