Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
目的：新的精神活性物质，如N-乙基戊酮（NEP）在非法药物市场上不断涌现，以及它们的影响和风险的知识，可能因性别而异，是稀缺的。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。
方法：精神兴奋剂，通过跟踪运动活动来研究奖励和增强效果，条件性位置偏好(CPP)范式，并通过自我管理(SA)程序，分别,在CD1小鼠中。此外，早期基因的表达(C-fos，电弧,Csnk1e,Pdyn,通过qPCR评估成瘾相关大脑区域中的Pp1r1b和Bdnf）。最后,通过UHPLC-MS/MS测定血清和脑NEP水平。
结果：接受NEP治疗的男性进行了运动敏化试验，与女性相比，反复给药后运动能力增加和高热。此外，虽然男女在CPP中的偏好得分相似，灭绝发生在后来，男性更容易复职。雌性小鼠在较高剂量下自我施用比雄性更多的NEP。早期基因表达的差异（Arc，Bdnf,Csnk1e和Ppp1r1b)被发现，但是血清和大脑NEP水平在性别之间没有差异。
结论：我们的结果表明，雄性小鼠对NEP精神兴奋剂和奖励效应更敏感。这些差异可能归因于不同的早期基因表达，而不是药代动力学因素。此外，男性似乎更容易受到NEP的高温影响，而女性可能更容易受到NEP的虐待。
方法：精神兴奋剂，通过跟踪运动活动来研究奖励和增强效果，条件性位置偏好(CPP)范式，并通过自我管理(SA)程序，分别,在CD1小鼠中。此外，早期基因的表达(C-fos，电弧,Csnk1e,Pdyn,通过qPCR评估成瘾相关大脑区域中的Pp1r1b和Bdnf）。最后,通过UHPLC-MS/MS测定血清和脑NEP水平。
结果：接受NEP治疗的男性进行了运动敏化试验，与女性相比，反复给药后运动能力增加和高热。此外，虽然男女在CPP中的偏好得分相似，灭绝发生在后来，男性更容易复职。雌性小鼠在较高剂量下自我施用比雄性更多的NEP。早期基因表达的差异（Arc，Bdnf,Csnk1e和Ppp1r1b)被发现，但是血清和大脑NEP水平在性别之间没有差异。
结论：我们的结果表明，雄性小鼠对NEP精神兴奋剂和奖励效应更敏感。这些差异可能归因于不同的早期基因表达，而不是药代动力学因素。此外，男性似乎更容易受到NEP的高温影响，而女性可能更容易受到NEP的虐待。
