Yueju pill and its active component- Myricetin attenuate the reinstatement of methamphetamine-seeking behavior in mice

Yueju pill (YJ), a traditional Chinese medicine, is widely used for the treatment of depression and pain due to its ability to prevent neuroinflammatory responses, regulate synaptic plasticity, and enhance cognitive function. Methamphetamine (METH) addiction is a chronic brain disease associated with inflammation and aberrant synaptic plasticity. However, whether and how YJ with its active components attenuates the METH-induced behavior remain unclear. In this study, we demonstrated that YJ attenuated the reinstatement of METH-seeking behavior while decreasing the activity of hippocampal CA1 neurons. Furthermore, YJ prevented METH-induced aberrant potentiation of glutamatergic transmission and restored physiological synaptic plasticity, likely mediated by upregulated expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95). Importantly, hippocampal CA1-specific knockdown of BDNF abolished the protective effects of YJ on METH-seeking behavior and synaptic dysfunction, confirming BDNF's pivotal role in YJ's mechanism of action. Mechanistically, YJ exerts its therapeutic effects by suppressing NLRP3 inflammasome activation. Notably, pharmacological activation of NLRP3 counteracted YJ-induced BDNF upregulation, suggesting that YJ restores synaptic plasticity, at least in part, through NLRP3 inhibition and subsequent microglial inactivation. Among its bioactive constituents, myricetin was identified as a key component responsible for reducing METH-seeking behavior and inflammatory responses. Collectively, our findings reveal that YJ attenuates aberrant synaptic plasticity by downregulating the NLRP3 inflammasome and enhancing BDNF expression in the hippocampus. These insights highlight the potential of targeting neuroimmune pathways and synaptic plasticity to develop novel therapeutic strategies for METH addiction.