Núria Nadal-Gratacós , Sandra Mata , Pol Puigseslloses , Morgane De Macedo , Virginie Lardeux , Stephanie Pain , Fu-Hua Wang , Liselott Källsten , David Pubill , Xavier Berzosa , Jan Kehr , Marcello Solinas , Jordi Camarasa , Elena Escubedo , Raul López-Arnau
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引用次数: 0
Abstract
Synthetic cathinones are emerging psychoactive substances designed to mimic the effects of classical psychostimulants. Among them, α-D2PV, a novel pyrrolidine-containing cathinone characterized by a phenyl group on the α-carbon atom, has gained significant attention. This study investigates the in vitro and in silico mechanism of action as well as the abuse liability of α-D2PV using rodent models. Dopamine (DA), noradrenaline (NE), and serotonin (5-HT) uptake inhibition assays were conducted in HEK293 cells expressing the corresponding human monoamine transporter, complemented by molecular docking studies at the DA transporter (DAT). Behavioral studies in male Swiss CD-1 mice assessed locomotor activity and conditioned place preference, while microdialysis and self-administration experiments were performed in male Sprague-Dawley rats. The findings reveal that α-D2PV is a potent DA and NE uptake inhibitor, with minimal activity at the 5-HT transporter (SERT). Docking studies showed that the benzene rings of α-PVP and α-D2PV align precisely in their most stable conformations at DAT. In vivo, α-D2PV elicited dose-dependent hyperlocomotion, thigmotaxis, and rewarding effects in mice, alongside increased extracellular DA levels in the nucleus accumbens of awake rats. Self-administration experiments confirmed α-D2PV's high reinforcing efficacy, indicating a significant risk of abuse in humans. Finally, these results underscore the necessity for continued surveillance of α-D2PV within the illicit drug market. Furthermore, novel synthetic cathinones incorporating a phenyl ring at the α-carbon side chain warrant proactive monitoring due to their potential to retain dopaminergic activity and evade initial legal controls.
期刊介绍:
Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).