Role of tissue plasminogen activator in the sensitization of methamphetamine-induced dopamine release in the nucleus accumbens

Ayumi Fukakusa, Taku Nagai, Hiroyuki Mizoguchi, Noboru Otsuka, Haruhide Kimura, Hiroyuki Kamei, Hyoung Chun Kim, Toshitaka Nabeshima, Kazuhiro Takuma, Kiyofumi Yamada

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We have previously demonstrated that repeated, but not acute, methamphetamine (METH) treatment increases tissue plasminogen activator (tPA) activity in the brain, which is associated with the development of behavioral sensitization to METH. In this study, we investigated whether the tPA-plasmin system is involved in the development of sensitization in METH-induced dopamine release in the nucleus accumbens (NAc). There was no difference in acute METH-induced increase in extracellular dopamine levels in the NAc between wild-type and tPA-deficient (tPA-/-) mice. Repeated METH treatment resulted in a significant enhancement of METH- induced dopamine release in wild-type mice, but not tPA-/- mice. Microinjection of exogenous tPA or plasmin into the NAc of wild-type mice significantly potentiated acute METH- induced dopamine release. Degradation of laminin was evident in brain tissues incubated with tPA plus plasminogen or plasmin in vitro although tPA or plasminogen alone had no effect. Immunohistochemical analysis revealed that microinjection of plasmin into the NAc reduced laminin immunoreactivity without neuronal damage. Our findings suggest that the tPA-plasmin system participates in the development of behavioral sensitization induced by repeated METH treatment, by regulating the processes underlying the sensitization of METH-induced dopamine release in the NAc, in which degradation of laminin by plasmin may play a role.

Original languageEnglish
Pages (from-to)436-444
Number of pages9
JournalJournal of Neurochemistry
Issue number2
Publication statusPublished - 01-04-2008
Externally publishedYes


All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

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