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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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. 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引用次数: 0
摘要
合成卡西酮是新出现的精神活性物质,旨在模仿传统精神兴奋剂的效果。其中,α-D2PV 是一种新型的含吡咯烷的卡西酮,其特点是在α-碳原子上有一个苯基,因此备受关注。本研究利用啮齿动物模型研究了 α-D2PV 的体外和体内作用机制以及滥用责任。在表达相应人类单胺转运体的 HEK293 细胞中进行了多巴胺(DA)、去甲肾上腺素(NE)和血清素(5-HT)摄取抑制试验,并对 DA 转运体(DAT)进行了分子对接研究。在雄性瑞士 CD-1 小鼠中进行的行为研究评估了运动活动和条件性地点偏好,而在雄性 Sprague-Dawley 大鼠中进行的微透析和自我给药实验则评估了运动活动和条件性地点偏好。研究结果表明,α-D2PV 是一种强效的 DA 和 NE 摄取抑制剂,对 5-HT 转运体(SERT)的活性极低。对接研究表明,α-PVP 和 α-D2PV 的苯环在 DAT 上以最稳定的构象精确地排列在一起。在小鼠体内,α-D2PV 可引起剂量依赖性的过度运动、移行和奖赏效应,同时还能增加清醒大鼠伏隔核中的细胞外 DA 水平。自我给药实验证实了α-D2PV的高强化效力,这表明它在人体中存在很大的滥用风险。最后,这些结果突出表明有必要继续监控非法药物市场中的α-D2PV。此外,在α-碳侧链上含有一个苯基环的新型合成卡西酮也值得积极监测,因为它们有可能保留多巴胺活性并逃避最初的法律管制。
Unveiling the potential abuse liability of α-D2PV: A novel α-carbon phenyl-substituted synthetic cathinone
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).