4-FLUOROETHYLPHENIDATE-INDUCED ADDICTIVE-LIKE BEHAVIOR INVOLVES D1 RECEPTOR-MEDIATED DOPAMINERGIC SIGNALING

4-Fluoroethylphenidate (4F-EPH) is a methylphenidate derivative functioning as a CNS stimulant. Psychostimulants including 4F-EPH produce rewarding and addictive-like effects through dopaminergic signaling. However, the pharmacological properties of 4F-EPH and the specific dopaminergic pathways mediating its abuse potential remain poorly understood. In this study, in vitro assays characterized the pharmacological profile of 4F-EPH by measuring dopamine transporter (DAT) and norepinephrine transporter (NET) inhibition. To assess the abuse potential of 4F-EPH, conditioned place preference (CPP) and behavioral sensitization (BS) paradigms were employed in mice. To elucidate the involvement of dopaminergic pathways, pharmacological antagonism of D1 and D2 receptors was conducted during CPP. Selective chemogenetic inhibition of D1 receptor-expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc) of D1-Cre mice was also performed. 4F-EPH potently inhibited DAT and NET, exhibiting greater DAT potency. In behavioral assays, 4F-EPH produced significant CPP, reaching peak reward effects at 10 mg/kg. Repeated 4F-EPH administration induced BS with progressive enhancement of locomotor activity that was maintained upon challenge after withdrawal. Pharmacological antagonism revealed D1 receptor specificity: D1 receptor antagonist SCH23390 suppressed CPP formation, whereas D2 receptor antagonist raclopride was ineffective. hM4Di-mediated chemogenetic inhibition of D1-expressing neurons in the NAc of D1-Cre mice prevented CPP formation, establishing the causal role of D1 signaling. These findings demonstrate 4F-EPH's substantial abuse potential and establish D1 receptor-mediated dopaminergic signaling in the NAc as the critical mechanism underlying its addictive behavior. [Supported by the NRF (RS-2025-16067597) and the MFDS (23212MFDS218) of Korea.]