Reduction of methamphetamine-induced sensitization and reward in matrix metalloproteinase-2 and -9-deficient mice

Hiroyuki Mizoguchi, Kiyofumi Yamada, Minae Niwa, Akihiro Mouri, Tomoko Mizuno, Yukihiro Noda, Atsumi Nitta, Shigeyoshi Itohara, Yoshiko Banno, Toshitaka Nabeshima

Research output: Contribution to journalArticlepeer-review


Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) function to remodel the pericellular environment. Their activation and regulation are associated with synaptic physiology and pathology. Here, we investigated whether MMP-2 and MMP-9 are involved in the rewarding effects of and sensitization to methamphetamine (METH) in animals, in which the remodelling of neural circuits may play a crucial role. Repeated METH treatment induced behavioural sensitization, which was accompanied by an increase in MMP-2 and MMP-9 activity in the brain. In MMP-2- and MMP-9-deficient mice [MMP-2-(-/-) and MMP-9-(-/-)], METH-induced behavioural sensitization and conditioned place preference, a measure of the rewarding effect, as well as METH-increased dopamine release in the nucleus accumbens (NAc) were attenuated compared with those in wild-type mice. In contrast, infusion of purified human MMP-2 into the NAc significantly potentiated the METH-increased dopamine release. The [3H]dopamine uptake into striatal synaptosomes was reduced in wild-type mice after repeated METH treatment, but METH-induced changes in [3H]dopamine uptake were significantly attenuated in MMP-2-(-/-) and MMP-9-(-/-) mice. These results suggest that both MMP-2 and MMP-9 play a crucial role in METH-induced behavioural sensitization and reward by regulating METH-induced dopamine release and uptake in the NAc.

Original languageEnglish (US)
Pages (from-to)1579-1588
Number of pages10
JournalJournal of Neurochemistry
Issue number6
StatePublished - Mar 2007


  • Dopamine
  • Drug dependence
  • Matrix metalloproteinases
  • Methamphetamine

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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