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

91 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

Fingerprint

Fibrinolysin
Tissue Plasminogen Activator
Morphine
Dopamine
Nucleus Accumbens
Plasminogen
Neuronal Plasticity
Extracellular Matrix Proteins
Microinjections
Serine Proteases
Naloxone
Peptide Hydrolases
Central Nervous System
Messenger RNA
Enzymes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Nagai, Taku ; Yamada, Kiyofumi ; Yoshimura, Masako ; Ishikawa, Kazuhiro ; Miyamoto, Yoshiaki ; Hashimoto, Kazuki ; Noda, Yukihiro ; Nitta, Atsumi ; Nabeshima, Toshitaka. / The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 10. pp. 3650-3655.
@article{b3fa3d1accf44bce8f82452bdeeb45ae,
title = "The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release",
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.",
author = "Taku Nagai and Kiyofumi Yamada and Masako Yoshimura and Kazuhiro Ishikawa and Yoshiaki Miyamoto and Kazuki Hashimoto and Yukihiro Noda and Atsumi Nitta and Toshitaka Nabeshima",
year = "2004",
month = "3",
day = "9",
doi = "10.1073/pnas.0306587101",
language = "English",
volume = "101",
pages = "3650--3655",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "10",

}

The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. / Nagai, Taku; Yamada, Kiyofumi; Yoshimura, Masako; Ishikawa, Kazuhiro; Miyamoto, Yoshiaki; Hashimoto, Kazuki; Noda, Yukihiro; Nitta, Atsumi; Nabeshima, Toshitaka.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 10, 09.03.2004, p. 3650-3655.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release

AU - Nagai, Taku

AU - Yamada, Kiyofumi

AU - Yoshimura, Masako

AU - Ishikawa, Kazuhiro

AU - Miyamoto, Yoshiaki

AU - Hashimoto, Kazuki

AU - Noda, Yukihiro

AU - Nitta, Atsumi

AU - Nabeshima, Toshitaka

PY - 2004/3/9

Y1 - 2004/3/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=1542723379&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1542723379&partnerID=8YFLogxK

U2 - 10.1073/pnas.0306587101

DO - 10.1073/pnas.0306587101

M3 - Article

C2 - 14988509

AN - SCOPUS:1542723379

VL - 101

SP - 3650

EP - 3655

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 10

ER -