Regulation by tissue plasminogen activator of rewarding effects of drugs of abuse

Taku Nagai, Kazuhiro Takuma, Toshitaka Nabeshima, Kiyofumi Yamada

Research output: Contribution to journalReview articlepeer-review


Drugs of abuse acutely modulate the activity of mesolimbic dopaminergic neurons, projecting from the ventral tegmental area of the midbrain to the nucleus accumbens (NAc). Tissue plasminogen activator (tPA) is a serine protease that catalyzes the conversion of plasminogen (pig) to plasmin. Here we show that this protease system participates in the rewarding effects of morphine, methamphetamine (METH) and nicotine. A single morphine treatment induces tPA mRNA and protein expression in the NAc. Morphine-induced conditioned place preference and hyperlocomotion are significantly reduced in tPA-deficient (tPA-/-) and pig-deficient (pig-/-) mice, being accompanied by a loss of morphine-induced dopamine release in the NAc. Repeated METH treatment also induces tPA mRNA expression in the NAc. METH-induced conditioned place preference and behavioral sensitization after repeated METH treatment are significantly reduced in tPA-/- mice compared with those in wild-type mice. Finally, we show that the tPA-plasmin system regulates nicotine-induced reward and dopamine release by activating protease activated receptor-1 (PAR1). Nicotine-induced dopamine release is markedly diminished in tPA-/- mice. Furthermore, plasmin activates PAR1 and nicotine-induced conditioned place preference and dopamine release are diminished in PAR1-deficient mice. Our findings suggest that targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches to the treatment of drug dependence.

Original languageEnglish
Pages (from-to)1-6
Number of pages6
JournalJapanese Journal of Neuropsychopharmacology
Issue number1
Publication statusPublished - 01-02-2008

All Science Journal Classification (ASJC) codes

  • Clinical Psychology
  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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