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Rationale <p>4-Fluoroethylphenidate (4&#xa0;F-EPH) is a novel synthetic psychostimulant structurally similar to ethylphenidate, recently detected in illicit drug markets. Its abuse liability remains unclear.</p> Objectives <p>This study aimed to evaluate the abuse-related behavioral effects of 4&#xa0;F-EPH in rodents using various preclinical models.</p> Methods <p>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 4 F-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 min after 4 F-EPH administration (0.01, 0.1, 1, 10 and 40 mg/kg). Intravenous self-administration (SA) was used to examine reinforcing effects under a fixed-ratio 1 and 2 schedule with 1 or 4 mg/kg/infusion. </p> Results <p>4&#xa0;F-EPH fully substituted for METH and cocaine with ED₅₀ values of 1.655&#xa0;mg/kg and 2.043&#xa0;mg/kg, respectively. In CPP, significant place preference was seen at 10 and 40&#xa0;mg/kg. Locomotor activity increased dose-dependently, peaking at 10&#xa0;mg/kg. Mice reliably self-administered 1&#xa0;mg/kg of 4&#xa0;F-EPH; however, the 4&#xa0;mg/kg dose reduced intake, possibly due to aversive or rate-limiting effects.</p> Conclusions <p>4&#xa0;F-EPH displays strong METH- and cocaine-like interoceptive effects, rewarding potential, and reinforcing properties, indicating a high abuse potential. Further toxicological evaluation is warranted.</p>

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Discriminative stimulus, rewarding, and reinforcing effects of 4-Fluoroethylphenidate in rodents

  • 期刊论文

  • 发表日期：

    2026年4月2日

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  • Min Gyeong Kim,
  • Hyun Kyu Min,
  • Son Seung Won,
  • Si-Keun Lim,
  • Ki Kyung Jung

摘要

Rationale

4-Fluoroethylphenidate (4 F-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 4 F-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 4 F-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 min after 4 F-EPH administration (0.01, 0.1, 1, 10 and 40 mg/kg). Intravenous self-administration (SA) was used to examine reinforcing effects under a fixed-ratio 1 and 2 schedule with 1 or 4 mg/kg/infusion.

Results

4 F-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 4 F-EPH; however, the 4 mg/kg dose reduced intake, possibly due to aversive or rate-limiting effects.

Conclusions

4 F-EPH displays strong METH- and cocaine-like interoceptive effects, rewarding potential, and reinforcing properties, indicating a high abuse potential. Further toxicological evaluation is warranted.