Neuropharmacological and behavioral characterization of 3F-phenetrazine, a novel amphetamine-like substance, in male mice and rats

3-Fluorophenetrazine (3F-phenetrazine) is a novel amphetamine-like substance that is structurally similar to phenmetrazine and 3F-phenmetrazine. Despite the emergence of 3F-phenetrazine in recreational drug markets, its neuropharmacological profile and abuse liability remain poorly characterized. This study is the first to investigate the psychostimulant, rewarding, and reinforcing properties of 3F-phenetrazine in male rodents using open-field test, conditioned place preference, and self-administration tests. In addition to the behavioral assessments, we analyzed serotonin levels, c-Fos and activity-regulated cytoskeleton-associated protein (Arc) expression, and dendritic spine density in the dorsal striatum and nucleus accumbens following acute or repeated 3F-phenetrazine administration in mice. Body weight changes during 3F-phenetrazine treatment and withdrawal periods were also evaluated in normal mice. Acute 3F-phenetrazine administration significantly increased locomotor activity, whereas repeated 3F-phenetrazine administration induced behavioral sensitization in mice. In the conditioned place preference and self-administration studies, 3F-phenetrazine produced a significant drug-paired place preference in mice and supported self-administration in rats, confirming its potent rewarding and reinforcing properties. Neurochemical analysis revealed that 3F-phenetrazine administration increased serotonin levels, c-Fos and Arc expression, and dendritic spine density in the dorsal striatum and/or nucleus accumbens, indicating that acute neurochemical alteration and addiction-related neuroplasticity occurred after repeated administration. Finally, 3F-phenetrazine treatment did not affect body weight. Collectively, these findings demonstrate that 3F-phenetrazine exerts significant psychostimulant, rewarding, and reinforcing effects via serotonergic neurotransmission and addiction-related neuroplastic changes in the dorsal striatum and/or nucleus accumbens. This study provides critical scientific evidence for the high abuse liability of 3F-phenetrazine, underscoring the need for legal regulation of its nonmedical use.