Sex differences in the effects of N-ethylpentylone in youngCD1 mice: insights on behaviour, thermoregulation andearly gene expression

Abstract

Background and Purpose: New psychoactive substances such as N-ethylpentylone(NEP) are continuously emerging in the illicit drug market, and knowledge of theireffects and risks, which may vary between sexes, is scarce. Our present study comparessome key effects of NEP in male and female mice.Experimental Approach: Psychostimulant, rewarding and reinforcing effects wereinvestigated by tracking locomotor activity, conditioned place preference (CPP) paradigmand through a self-administration (SA) procedure, respectively, in CD1 mice.Moreover, the expression of early genes (C-fos, Arc, Csnk1e, Pdyn, Pp1r1b and Bdnf inaddiction-related brain areas) was assessed by qPCR. Finally, serum and brain levelsof NEP were determined by UHPLC-MS/MS.Key Results: NEP-treated males experimented locomotor sensitisation and showedhigher and longer increases in locomotion as well as higher hyperthermia afterrepeated administration than females. Moreover, while preference score in the CPPwas similar in both sexes, extinction occurred later, and reinstatement was more easilyestablished for males. Female mice self-administered more NEP than males at ahigher 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.Conclusion and Implications: Our results suggest that male mice are more sensitiveto NEP psychostimulant and rewarding effects. These differences may be attributedto different early gene expression but not to pharmacokinetic factors. Moreover,males appear to be more vulnerable to the hyperthermic effects of NEP, whilefemales might be more prone to NEP abuse.