Pharmacological characterization of 4-F-3-Me-α-PVP: A novel synthetic cathinone with psychostimulant effects and abuse liability in rodents

Background: The continual emergence of novel synthetic cathinones poses significant public health concerns due to their unpredictable pharmacological profiles and potential for abuse. Among these, 4-F-3-Me-α-PVP—a newly identified analogue of α-PVP—has recently surfaced on the illicit drug market, yet its biological effects remain uncharacterized. Aim: To provide the first comprehensive pharmacological evaluation of 4-F-3-Me-α-PVP. Methods: In vitro transporter inhibition was assessed using HEK293 cells expressing human dopamine (DA), norepinephrine, and serotonin transporter (DAT, NET, or SERT). In male rodents, locomotor activity was measured after i.p. (mice) or s.c. (rats) administration. In vivo microdialysis in rats quantified extracellular DA in the nucleus accumbens. Rewarding and reinforcing effects were evaluated using conditioned place preference (CPP) in mice and intravenous self-administration (IVSA) in rats under fixed-ratio and progressive-ratio schedules. Results: In vitro assays revealed that 4-F-3-Me-α-PVP acts as a potent DAT and NET inhibitor, with additional, though weaker, activity at SERT. In vivo, 4-F-3-Me-α-PVP significantly increased locomotor activity in male rodents (10 and 30 mg/kg in mice; 3 mg/kg in rats). Importantly, 4-F-3-Me-α-PVP also increased extracellular DA levels in the rat nucleus accumbens (3 mg/kg, s.c.), pointing to its potential for abuse. Behavioral assays further demonstrated rewarding and reinforcing effects in rodents, with significant CPP in mice at all doses tested and dose-dependent IVSA in rats observed under both fixed-ratio and progressive-ratio schedules. Conclusions: Collectively, these findings indicate that 4-F-3-Me-α-PVP possesses substantial psychostimulant and abuse-related effects in rodents, underscoring the need for regulatory vigilance and continued investigation into emerging synthetic cathinones.