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

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.