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

PLoS One. 2014 Jun 5;9(6):e98981. doi: 10.1371/journal.pone.0098981. eCollection 2014.

Abstract

Goal: To investigate the effect of luteolin on methamphetamine (MA)-induced behavioral sensitization and mitogen-activated 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Luteolin / pharmacology*
  • Male
  • Methamphetamine / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Motor Activity / drug effects
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Putamen / drug effects
  • Putamen / metabolism*
  • Signal Transduction / drug effects*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Fosb protein, mouse
  • Proto-Oncogene Proteins c-fos
  • Methamphetamine
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Luteolin

Grants and funding

National Natural Science Foundation of China (No. 81273351), National Natural Science Foundation of China (No. 81373253; http://www.nsfc.gov.cn). 2012 Key Program for International S&T Cooperation Projects of Shaanxi Province (2012kw-36-02; http://www.sninfo.gov.cn). The Fundamental Research Funds for the Central Universities, Shaanxi Key Project on Science and Technology (2013K12-01-09; http://www.xjtu.edu.cn). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.