Neurochemical and behavioral evidence of high abuse liability of 3F-NEB, a novel synthetic cathinone

Synthetic cathinones constitute a major class of New Psychoactive Substances (NPS) with significant abuse potential. Within this class, 3F-N-ethylbuphedrone (3F-NEB or 2-(ethylamino)-1-(3-fluorophenyl)butan-1-one), a novel N-ethyl buphedrone derivative, has recently emerged in recreational drug markets. However, its pharmacological properties and abuse liability remain uncharacterized. The present study aimed to evaluate the neurochemical mechanisms and behavioral effects of 3F-NEB to assess its potential for abuse and addiction. To this end, we conducted in vitro monoamine uptake inhibition assays and in mice we performed locomotor activity and conditioned place preference tests. In rats, we conducted in vivo microdialysis in the nucleus accumbens, intravenous self-administration, and assessed neuroadaptive changes by ΔFosB immunohistochemistry following chronic self-administration. Our results demonstrate that 3F-NEB acts as a potent dopamine transporter (DAT) inhibitor, with more than 100-fold selectivity over the serotonin transporter (SERT). Acute administration (3 mg/kg) rapidly increased extracellular dopamine levels in the nucleus accumbens of rats. At the behavioral level, 3F-NEB induced dose-dependent locomotor increases (10–30 mg/kg), with anxiety-like effects at the highest doses, and conditioned place preference at all tested doses (3–30 mg/kg) in mice. 3F-NEB was readily self-administered by rats under both fixed-ratio and progressive-ratio schedules. Furthermore, chronic self-administration significantly increased ΔFosB expression in dorsomedial and dorsolateral striatum, mirroring patterns observed with methamphetamine. Taken together, these results demonstrate that 3F-NEB exhibits potent dopaminergic activity and high abuse liability through selective dopamine transporter inhibition. The compound's robust reinforcing properties and induction of addiction-related molecular adaptations suggest significant public health risks warranting immediate regulatory control.