Swiss-Webster and C57BL/6 mice are differentially sensitive to the stimulant effects of methamphetamine.

Methamphetamine is a highly addictive psychostimulant with significant neurobiological consequences, yet strain-dependent differences in its effects remain poorly understood. This study investigated behavioral and molecular differences in Swiss-Webster and C57BL/6 mice following methamphetamine exposure. Swiss-Webster mice exhibited greater behavioral sensitivity to methamphetamine compared to C57BL/6 mice, as demonstrated by lower peak doses required to elicit locomotor stimulation and conditioned place preference. Gene expression analyses revealed significantly higher striatal dopamine D2 receptor mRNA levels in Swiss-Webster mice, alongside a main effect of strain across multiple dopaminergic receptors, suggesting broader transcriptional differences may contribute to their heightened behavioral response. However, no strain differences were observed in dopamine transporter or dopamine D1 receptor mRNA expression. Following a neurotoxic binge-dosing regimen, both strains showed significant dopamine depletion, but no differences in the dopamine metabolite DOPAC were observed between strains in the striatum. Given the role of dopaminergic signaling in stimulant sensitivity and reward, these findings suggest that strain-dependent differences in methamphetamine response may reflect broader alterations in dopamine system function between these strains. This is the first study to directly compare Swiss-Webster and C57BL/6 mice in methamphetamine-induced CPP and provides novel insight into strain-specific drug reward mechanisms.