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

doi:10.1073/pnas.0306587101

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

^*Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; and ^‡Laboratory of Neuropsychopharmacology, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-0934, Japan

Edited by Solomon H. Snyder, John Hopkins University School of Medicine, Baltimore, MD, and approved January 8, 2004 (received for review October 11, 2003)

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.

Footnotes

↵ § To whom correspondence may be addressed. E-mail: kyamada{at}p.kanazawa-u.ac.jp or tnabeshi{at}med.nagoya-u.ac.jp.
↵ † T.N. and K.Y. contributed equally to this work.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: plg, plasminogen; tPA, tissue plg activator; NAcc, nucleus accumbens; VTA, ventral tegmental area.