Methamphetamine conditioned place preference in adolescent mice: Interaction between sex and strain

J Psychopharmacol. 2026 Feb 28:2698811261420102. doi: 10.1177/02698811261420102. Online ahead of print.

ABSTRACT

BACKGROUND: Methamphetamine (METH) use is higher in adolescent women than adolescent men. While rodent studies support a sex difference in the reinforcing effects of METH, few have investigated sex differences in the underlying neural circuits, none of which tested rodents during adolescence.

AIMS: Investigate whether there are sex differences in the rewarding effects of METH in two strains of adolescent mice that are commonly used to generate transgenic lines. Identify changes in associated neural circuits.

METHODS: We tested METH-induced conditioned place preference (CPP) in male and female 129Sv/Ev and C57Bl/6 mice during middle adolescence using 1 mg/kg of METH. Cells expressing c-Fos protein were quantified in the nucleus accumbens (NAc) and area CA1 of the hippocampus following the postconditioning test.

RESULTS: In C57Bl/6 mice, METHinduced CPP in females, but not males. Conversely, METHinduced CPP in 129Sv/Ev males, but not females. In both strains, groups that exhibited CPP had more c-Fos+ cells in the NAc and CA1 than saline-treated control groups. The number of c-Fos+ cells in these two brain regions only correlated in groups that exhibited CPP. Finally, we found evidence of behavioral sensitization in 129Sv/Ev males only.

CONCLUSIONS: Our study reveals that the rewarding effects of METH in adolescent mice are both sex- and strain-dependent, indicating that behavioral and neural responses to METH may result from an interaction between sex-specific and genetic mechanisms. Our work will guide the selection of appropriate background strains in future studies using genetically modified mice.

PMID:41763884 | DOI:10.1177/02698811261420102