The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release

Taku Nagai, Kiyofumi Yamada, Masako Yoshimura, Kazuhiro Ishikawa, Yoshiaki Miyamoto, Kazuki Hashimoto, Yukihiro Noda, Atsumi Nitta, Toshitaka Nabeshima

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

Tissue plasminogen activator (tPA) is a serine protease that catalyzes the conversion of plasminogen (plg) to plasmin, which in turn functions to degrade extracellular matrix proteins in the central nervous system. The tPA-plasmin system plays a role in synaptic plasticity and remodeling. Here we show that this protease system participates in the rewarding effects of morphine by acutely regulating morphine-induced dopamine release in the nucleus accumbens (NAcc). A single morphine treatment induced tPA mRNA and protein expression in a naloxone-sensitive manner, which was associated with an increase in the enzyme activity in the NAcc. The acute effect of morphine in inducing tPA expression was diminished after repeated administration. Morphine-induced conditioned place preference and hyperlocomotion were significantly reduced in tPA-/- and plg-/- mice, being accompanied by a loss of morphine-induced dopamine release in the NAcc. The defect of morphine-induced dopamine release and hyperlocomotion in tPA-/- mice was reversed by microinjections of either exogenous tPA or plasmin into the NAcc. Our findings demonstrate a previously undescribed function of the tPA-plasmin system in regulating dopamine release, which is involved in the rewarding effects of morphine.

Original languageEnglish
Pages (from-to)3650-3655
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number10
DOIs
Publication statusPublished - 09-03-2004

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release'. Together they form a unique fingerprint.

  • Cite this