The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release.
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.
Nagai
Taku
T
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
Yamada
Kiyofumi
K
Yoshimura
Masako
M
Ishikawa
Kazuhiro
K
Miyamoto
Yoshiaki
Y
Hashimoto
Kazuki
K
Noda
Yukihiro
Y
Nitta
Atsumi
A
Nabeshima
Toshitaka
T
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D005341:Fibrinolysin / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D012333:RNA, Messenger; D009020:Morphine; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D004298:Dopamine