Psilocin suppresses methamphetamine‐induced hyperlocomotion and acquisition of conditioned place preference via D2R‐mediated ERK signaling

AIM: Psilocin is an active metabolite form of psilocybin and exerts psychoactive effects. Recent studies suggest that psilocin may have regulatory effects on abuse drugs, but the mechanisms remain unclear. In this study, we want to explore the effects of psilocin on methamphetamine (METH)‐induced alterations of behavior in mice and its molecular mechanisms. METHODS: Acute METH administration model and conditioned place preference (CPP) model were used to investigate the effects of psilocin on METH‐induced alterations of behavior. Western blot was used to detect the expression of proteins. RESULTS: In the acute 2 mg/kg METH administration model, 1 mg/kg psilocin counteracted METH‐induced elevation of activity. In the 1 mg/kg METH‐induced CPP model, 1 mg/kg psilocin inhibited CPP formation during the acquisition phase. However, psilocin did not impact METH extinction and relapse. Molecular results showed that the regulatory effect of psilocin on METH was underscored by altered expression of dopamine 2 receptor (D2R) and phosphorylated extra‐cellular signal‐regulated kinase (p‐ERK) in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Trifluoperazine (TFP)‐2HCl is a D2R inhibitor, and SCH772984 is a selective extra‐cellular signal‐regulated kinase (ERK) inhibitor that effectively inhibits ERK1/2 phosphorylation. The results indicated that 2 mg/kg TFP‐2HCl and 10 mg/kg SCH772984 blocked METH‐induced hyperactivity and acquisition of METH‐induced CPP. CONCLUSION: Psilocin has regulatory effects on METH‐induced alterations of behavior in mice via D2R‐mediated signal regulation of ERK phosphorylation.