Abstract
Valproate may hold promise as a treatment for addiction. However, there are limited studies examining the effects of magnesium valproate (VPA-Mg) on methamphetamine (MA) addiction, and the relevant mechanisms have not been thoroughly discussed. This study aims to explore the potential therapeutic effects of VPA-Mg on MA addiction and to investigate its possible mechanisms. The effects of VPA-Mg on MA addiction were investigated using conditioned place preference (CPP) and behavioural sensitisation models in rats. VPA-Mg was administered during CPP formation and extinction phases to evaluate its effects on MA-induced CPP formation and reinstatement. Behavioural sensitisation assessed the impact of VPA-Mg during sensitisation induction and expression phases, with spontaneous activity and MA dosing optimised beforehand. Furthermore, western blotting was performed on brain regions including the prefrontal cortex (PFC), hippocampus (Hip), nucleus accumbens (NAc) and ventral tegmental area (VTA) to measure glycogen synthase kinase 3 beta (GSK-3β) and dopamine transporter (DAT) protein levels. VPA-Mg did not exhibit a significant impact on MA-induced CPP formation. VPA-Mg significantly reduced the establishment and expression of MA-induced behavioural sensitisation (p < 0.01). Pre-treatment with VPA-Mg for 3 days before the expression period also inhibited sensitisation (p < 0.05). In addition, the ratio of p-GSK-3β to t-GSK-3β in the PFC, Hip and VTA of rats with behavioural sensitisation significantly decreased, and the expression of DAT decreased significantly (p < 0.01). VPA-Mg can reverse the increase in GSK-3β activity in the Hip and the decrease in DAT in the PFC and Hip caused by repeated MA use (p < 0.05). VPA-Mg exhibits anti-addictive effects on MA dependence and relapse prevention. GSK-3β activation and DAT downregulation in addiction-related brain regions (PFC, Hip, VTA) are closely linked to MA addiction, suggesting potential therapeutic targets. VPA-Mg may exert its effects by modulating these pathways, particularly in the PFC and Hip.