Luteolin Inhibits Behavioral Sensitization by Blocking Methamphetamine-Induced MAPK Pathway Activation in the Caudate Putamen in Mice

Abstract

GoalTo investigate the effect of luteolin on methamphetamine (MA)-induced behavioral sensitization and mitogen-activated protein kinase (MAPK) signal transduction pathway activation in mice.MethodsMice 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.ResultsLuteolin 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.ConclusionsLuteolin 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.

HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function

“…Adaptations in the CPu has been associated with methamphetamine sensitization (Li et al 2016a; Li et al 2016b; Yan et al 2014). However, the subdivisions of the striatum have important functional differences that need to be considered (Boekhoudt et al 2016).…”

Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) produced by chronic methamphetamine intake in rats

“…In a recent study, Yan et al (2014) demonstrated that the casein kinase 2-inhibitor luteolin inhibited behavioral sensitization by blocking methamphetamine-induced MAPK activation in the caudate putamen of mice. Given the similar observations from the present study, we propose a potential beneficial effect of ibudilast to attenuate methamphetamine-seeking during abstinence by reversing the levels the synaptic protein PEBP1.…”

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects

“…METH challenge after withdrawal from repeated METH exposure has been shown to induce behavioral sensitization related to pERK induction in both CPu and NAc as well as ΔFosB expression in the CPu 122,169,170 . The development and expression of METH behavioral sensitization and challenge-augmented pERK induction were inhibited by levo-tetrahydropalmatine, an antagonist of D1- and D2-Rs 169,171,172 , suggesting the involvement of DA receptors in chronic METH-induced pERK and behavioral sensitization.…”