Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacology Section, Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
Br J Pharmacol. 2024 Nov;181(22):4491-4513. doi: 10.1111/bph.16506. Epub 2024 Jul 16.
New psychoactive substances such as N-ethylpentylone (NEP) are continuously emerging in the illicit drug market, and knowledge of their effects and risks, which may vary between sexes, is scarce. Our present study compares some key effects of NEP in male and female mice.
Psychostimulant, rewarding and reinforcing effects were investigated by tracking locomotor activity, conditioned place preference (CPP) paradigm and through a self-administration (SA) procedure, respectively, in CD1 mice. Moreover, the expression of early genes (C-fos, Arc, Csnk1e, Pdyn, Pp1r1b and Bdnf in addiction-related brain areas) was assessed by qPCR. Finally, serum and brain levels of NEP were determined by UHPLC-MS/MS.
NEP-treated males experimented locomotor sensitisation and showed higher and longer increases in locomotion as well as higher hyperthermia after repeated administration than females. Moreover, while preference score in the CPP was similar in both sexes, extinction occurred later, and reinstatement was more easily established for males. Female mice self-administered more NEP than males at a higher dose. Differences in early gene expression (Arc, Bdnf, Csnk1e and Ppp1r1b) were found, but the serum and brain NEP levels did not differ between sexes.
Our results suggest that male mice are more sensitive to NEP psychostimulant and rewarding effects. These differences may be attributed to different early gene expression but not to pharmacokinetic factors. Moreover, males appear to be more vulnerable to the hyperthermic effects of NEP, while females might be more prone to NEP abuse.
新型精神活性物质如 N-乙基戊基酮（NEP）不断出现在非法毒品市场，其作用和风险的知识，可能因性别而异，还很缺乏。我们目前的研究比较了 NEP 在雄性和雌性小鼠中的一些关键作用。
通过跟踪运动活动、条件性位置偏好（CPP）范式和自我给药（SA）程序，分别在 CD1 小鼠中研究了兴奋剂、奖赏和强化作用。此外，通过 qPCR 评估了与成瘾相关脑区的早期基因（C-fos、Arc、Csnk1e、Pdyn、Pp1r1b 和 Bdnf）的表达。最后，通过 UHPLC-MS/MS 测定了血清和脑内 NEP 的水平。
与雌性相比，NEP 处理的雄性小鼠经历了运动敏化，并表现出更高和更长时间的运动增加以及更高的复发性体温升高。此外，虽然两性的 CPP 偏好评分相似，但雌性的消退出现较晚，雄性更容易建立复燃。雌性小鼠在更高剂量下自我给予的 NEP 比雄性更多。发现了早期基因表达（Arc、Bdnf、Csnk1e 和 Ppp1r1b）的差异，但性别之间的血清和脑内 NEP 水平没有差异。
我们的结果表明，雄性小鼠对 NEP 的兴奋剂和奖赏作用更为敏感。这些差异可能归因于不同的早期基因表达，但与药代动力学因素无关。此外，雄性似乎对 NEP 的体温升高作用更为敏感，而雌性可能更容易滥用 NEP。
