Polygalae Radix Attenuates Methamphetamine-Induced Behavioral Sensitization Through the TrkB/ERK Pathway in the Caudate Putamen of Mice

Methamphetamine (METH) addiction is a chronic brain disorder characterized by intense drug cravings and high relapse rates. Traditional Chinese medicines (TCM) have shown efficacy in treating METH addiction via TrkB/ERK signaling. However, the role of Polygalae Radix (PR), a neuropharmacological active TCM, in METH addiction remains unclear. This study examined the effects of PR (25, 50, and 100 mg/kg) on locomotor activity in mice and its impact on METH-induced behavioral sensitization (BS) at different stages. Western blotting (WB) assessed TrkB and ERK expression across brain regions. PR (25 and 50 mg/kg) alone had no effect on locomotor activity in mice, whereas 100 mg/kg significantly reduced locomotor activity. PR (25 and 50 mg/kg) administered during the development phase inhibited METH-induced locomotor activity, but its administration during the expression phase had no impact. Continuous PR (25 and 50 mg/kg) administration throughout the entire process prevented METH-induced BS in mice. WB analysis revealed that PR alone elevated ERK in the prefrontal cortex, nucleus accumbens (NAc), caudate putamen (CPu), and TrkB in the CPu. During the development phase, PR inhibited METH-induced TrkB/ERK increases in the CPu, whereas, during the expression phase, ERK elevation in the CPu was mitigated. Continuous PR administration blocked METH-induced TrkB/ERK increases in the CPu and ERK levels in the NAc. These findings indicate that PR attenuates METH-induced BS and locomotor activity during the developmental phase through the TrkB/ERK pathway in the CPu, highlighting its therapeutic potential for METH addiction.