Sex differences in the effects of N‐ethylpentylone in young CD1 mice: Insights on behaviour, thermoregulation and early gene expression

• Published in: British journal of pharmacology Vol. 181; no. 22; pp. 4491 - 4513
• Main Authors: Espinosa‐Velasco, María, Castro‐Zavala, Adriana, Reguilón, Marina D., Gallego‐Landin, Inés, Bellot, Marina, Rublinetska, Olga, Valverde, Olga, Rodríguez‐Arias, Marta, Nadal‐Gratacós, Núria, Berzosa, Xavier, Gómez‐Canela, Cristian, Carbó, Marcel·lí, Camarasa, Jorge, Escubedo, Elena, López‐Arnau, Raúl, Pubill, David
• Format: Journal Article
• Language: English
• Published: England 01.11.2024
• Subjects: addiction; Animals; Behavior, Animal - drug effects; Body Temperature Regulation - drug effects; Brain - drug effects; Brain - metabolism; ephylone; Female; Gene Expression - drug effects; Locomotion - drug effects; Male; Mice; new psychoactive substances; N‐ethylpentylone; Self Administration; Sex Characteristics; sex differences; synthetic cathinones; ephylone; N‐ethylpentylone; new psychoactive substances; sex differences; addiction; synthetic cathinones
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.16506

Background and Purpose 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. Experimental Approach 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. Key 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. Conclusion and Implications 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.