Discriminative Stimulus, Rewarding, and Reinforcing Effects of 4- Fluoroethylphenidate in Rodents

Discriminative Stimulus, Rewarding, and Reinforcing Effects of 4- Fluoroethylphenidate in Rodents | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Discriminative Stimulus, Rewarding, and Reinforcing Effects of 4- Fluoroethylphenidate in Rodents Min Gyeong Kim, Hyun Kyu Min, Son Seung Won, Si-Keun Lim, Ki Kyung Jung This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7637489/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Apr, 2026 Read the published version in Psychopharmacology → Version 1 posted You are reading this latest preprint version Abstract Rationale. 4-Fluoroethylphenidate (4F-EPH) is a novel synthetic psychostimulant structurally similar to ethylphenidate, recently detected in illicit drug markets. Its abuse liability remains unclear. Objectives. This study aimed to evaluate the abuse-related behavioral effects of 4F-EPH in rodents using various preclinical models. Methods. Drug discrimination tests were conducted in male Sprague-Dawley rats trained to differentiate methamphetamine (METH, 0.5 mg/kg) or cocaine (5.6 mg/kg) from saline, and 4F-EPH was subsequently tested for substitution at doses of 1, 2, and 5 mg/kg (i.p.) to assess its interoceptive similarity. Reward potential was assessed in C57BL/6J mice via the conditioned place preference (CPP) test at 1, 10, and 40 mg/kg. Locomotor activity was measured for 60 minutes after 4F-EPH administration (0.01, 0.1, 1, 10, 40 mg/kg). Intravenous self-administration (SA) was used to examine reinforcing effects under a fixed-ratio 1 schedule with 1 or 4 mg/kg/infusion. Results. 4F-EPH fully substituted for METH and cocaine with ED₅₀ values of 1.655 mg/kg and 2.043 mg/kg, respectively. In CPP, significant place preference was seen at 10 and 40 mg/kg. Locomotor activity increased dose-dependently, peaking at 10 mg/kg. Mice reliably self-administered 1 mg/kg of 4F-EPH; however, the 4 mg/kg dose reduced intake, possibly due to aversive or rate-limiting effects. Conclusions. 4F-EPH displays strong METH- and cocaine-like interoceptive effects, rewarding potential, and reinforcing properties, indicating a high abuse potential. Further toxicological evaluation is warranted. 4-Fluoroethylphenidate (4F-EPH) Drug discrimination Self-administration Conditioned Place Preference locomotor-activating Psychostimulant Drug abuse potential Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 02 Apr, 2026 Read the published version in Psychopharmacology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7637489","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":530304069,"identity":"931d695a-36ae-4d4d-90d5-d856330c7de3","order_by":0,"name":"Min Gyeong Kim","email":"","orcid":"","institution":"Sungkyunkwan University","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"Gyeong","lastName":"Kim","suffix":""},{"id":530304070,"identity":"7685dcef-1a56-4329-b422-b7d0c4f79734","order_by":1,"name":"Hyun Kyu Min","email":"","orcid":"","institution":"Ministry of Food and Drug 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Rodents","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"4-Fluoroethylphenidate (4F-EPH), Drug discrimination, Self-administration, Conditioned Place Preference, locomotor-activating, Psychostimulant, Drug abuse potential","lastPublishedDoi":"10.21203/rs.3.rs-7637489/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7637489/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eRationale.\u003c/strong\u003e 4-Fluoroethylphenidate (4F-EPH) is a novel synthetic psychostimulant structurally similar to ethylphenidate, recently detected in illicit drug markets. Its abuse liability remains unclear.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives.\u003c/strong\u003e This study aimed to evaluate the abuse-related behavioral effects of 4F-EPH in rodents using various preclinical models.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods.\u003c/strong\u003e Drug discrimination tests were conducted in male Sprague-Dawley rats trained to differentiate methamphetamine (METH, 0.5 mg/kg) or cocaine (5.6 mg/kg) from saline, and 4F-EPH was subsequently tested for substitution at doses of 1, 2, and 5 mg/kg (i.p.) to assess its interoceptive similarity. Reward potential was assessed in C57BL/6J mice via the conditioned place preference (CPP) test at 1, 10, and 40 mg/kg. Locomotor activity was measured for 60 minutes after 4F-EPH administration (0.01, 0.1, 1, 10, 40 mg/kg). Intravenous self-administration (SA) was used to examine reinforcing effects under a fixed-ratio 1 schedule with 1 or 4 mg/kg/infusion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults.\u003c/strong\u003e 4F-EPH fully substituted for METH and cocaine with ED₅₀ values of 1.655 mg/kg and 2.043 mg/kg, respectively. In CPP, significant place preference was seen at 10 and 40 mg/kg. Locomotor activity increased dose-dependently, peaking at 10 mg/kg. Mice reliably self-administered 1 mg/kg of 4F-EPH; however, the 4 mg/kg dose reduced intake, possibly due to aversive or rate-limiting effects.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions.\u003c/strong\u003e 4F-EPH displays strong METH- and cocaine-like interoceptive effects, rewarding potential, and reinforcing properties, indicating a high abuse potential. Further toxicological evaluation is warranted.\u003c/p\u003e","manuscriptTitle":"Discriminative Stimulus, Rewarding, and Reinforcing Effects of 4- Fluoroethylphenidate in Rodents","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-20 16:41:06","doi":"10.21203/rs.3.rs-7637489/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"39eb4bb2-df6c-4981-ba54-8f5f7ae581d4","owner":[],"postedDate":"October 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T16:03:35+00:00","versionOfRecord":{"articleIdentity":"rs-7637489","link":"https://doi.org/10.1007/s00213-026-07026-7","journal":{"identity":"psychopharmacology","isVorOnly":false,"title":"Psychopharmacology"},"publishedOn":"2026-04-02 15:58:40","publishedOnDateReadable":"April 2nd, 2026"},"versionCreatedAt":"2025-10-20 16:41:06","video":"","vorDoi":"10.1007/s00213-026-07026-7","vorDoiUrl":"https://doi.org/10.1007/s00213-026-07026-7","workflowStages":[]},"version":"v1","identity":"rs-7637489","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7637489","identity":"rs-7637489","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}