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Modafinil (<jats:styled-content style=\"fixed-case\">MOD<\/jats:styled-content>), like cocaine, is a dopamine reuptake inhibitor and one of the few drugs evaluated in clinical trials that has shown promise for the treatment of cocaine or methamphetamine use disorders in some patient subpopulations. Recent structure\u2013activity relationship and preclinical studies on a series of <jats:styled-content style=\"fixed-case\">MOD<\/jats:styled-content> analogs have provided insight into modifications of its chemical structure that may lead to advancements in clinical efficacy. Here, we have tested the effects of the clinically available (<jats:italic>R<\/jats:italic>)\u2010enantiomer of <jats:styled-content style=\"fixed-case\">MOD<\/jats:styled-content> on extracellular dopamine levels in the nucleus accumbens shell, a mesolimbic dopaminergic projection field that plays significant roles in various aspects of psychostimulant use disorders, measured <jats:italic>in\u00a0vivo<\/jats:italic> by fast\u2010scan cyclic voltammetry and by microdialysis in Sprague\u2010Dawley rats. We have compared these results with those obtained under identical experimental conditions with two novel and enantiopure bis(F) analogs of <jats:styled-content style=\"fixed-case\">MOD<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> JBG<\/jats:styled-content>1\u2010048 and <jats:styled-content style=\"fixed-case\">JBG<\/jats:styled-content>1\u2010049. The results show that (<jats:italic>R<\/jats:italic>)\u2010modafinil (R\u2010<jats:styled-content style=\"fixed-case\">MOD<\/jats:styled-content>), <jats:styled-content style=\"fixed-case\">JBG<\/jats:styled-content>1\u2010048, and <jats:styled-content style=\"fixed-case\">JBG<\/jats:styled-content>1\u2010049, when administered intravenously with cumulative drug\u2010doses, will block the dopamine transporter and reduce the clearance rate of dopamine, increasing its extracellular levels. Differences among the compounds in their maximum stimulation of dopamine levels, and in their time course of effects were also observed. These data highlight the mechanistic underpinnings of R\u2010<jats:styled-content style=\"fixed-case\">MOD<\/jats:styled-content> and its bis(F) analogs as pharmacological tools to guide the discovery of novel medications to treat psychostimulant use disorders.<\/jats:p>","DOI":"10.1111\/ejn.14256","type":"journal-article","created":{"date-parts":[[2018,11,7]],"date-time":"2018-11-07T08:44:50Z","timestamp":1541580290000},"page":"2045-2053","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Distinct effects of (<i>R<\/i>)\u2010modafinil and its (<i>R<\/i>)\u2010 and (<i>S<\/i>)\u2010fluoro\u2010analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats"],"prefix":"10.1111","volume":"50","author":[{"given":"Jacqueline D.","family":"Keighron","sequence":"first","affiliation":[{"name":"Medication Development Program Molecular Targets and Medications Discovery Branch Department of Health and Human Services National Institute on Drug Abuse Intramural Research Program National Institutes of Health 333 Cassell Drive, TRIAD Bldg. 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Baltimore MD 21224 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily M.","family":"DeMarco","sequence":"additional","affiliation":[{"name":"Medication Development Program Molecular Targets and Medications Discovery Branch Department of Health and Human Services National Institute on Drug Abuse Intramural Research Program National Institutes of Health 333 Cassell Drive, TRIAD Bldg. Baltimore MD 21224 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Coggiano","sequence":"additional","affiliation":[{"name":"Medication Development Program Molecular Targets and Medications Discovery Branch Department of Health and Human Services National Institute on Drug Abuse Intramural Research Program National Institutes of Health 333 Cassell Drive, TRIAD Bldg. 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