Luteolin inhibits behavioral sensitization by blocking methamphetamine- induced MAPK pathway activation in the caudate putamen in mice

Goal: To investigate the effect of luteolin on methamphetamine (MA)-induced behavioral sensitization and mitogenactivated protein kinase (MAPK) signal transduction pathway activation in mice. Methods: Mice received a single dose of MA to induce hyperactivity or repeated intermittent intraperitoneal injections of MA to establish an MA-induced behavioral sensitization mouse model. The effect of luteolin on the development and expression of MA-induced hyperactivity and behavioral sensitization was examined. The expression and activity of ΔFosB and the levels of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), phosphorylated c-Jun N-terminal kinase (pJNK), and phosphorylated p38 mitogen-activated protein kinase (pp38) in the caudate putamen (CPu) were measured by western blot. Results: Luteolin significantly decreased hyperactivity as well as the development and expression of MA-induced behavioral sensitization in mice. ΔFosB, pERK1/2, and pJNK levels in the CPu were higher in MA-treated mice than in control mice, whereas the pp38 level did not change. Injection of luteolin inhibited the MA-induced increase in ΔFosB, pERK1/2, and pJNK levels, but did not affect the pp38 level. Conclusions: Luteolin inhibits MA-induced hyperactivity and behavioral sensitization in mice through the ERK1/2/ΔFosB pathway. Furthermore, the JNK signaling pathway might be involved in MA-induced neurodegeneration in the CPu, and luteolin inhibits this process.