title: The rewards of nicotine: regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1.
abstract: Nicotine, a primary component of tobacco, is one of the most abused drugs worldwide. Approximately four million people die each year because of diseases associated with tobacco smoking. Mesolimbic dopaminergic neurons mediate the rewarding effects of abused drugs, including nicotine. Here we show that the tissue plasminogen activator (tPA)-plasmin system regulates nicotine-induced reward and dopamine release by activating protease activated receptor-1 (PAR1). In vivo microdialysis revealed that microinjection of either tPA or plasmin into the nucleus accumbens (NAc) significantly potentiated whereas plasminogen activator inhibitor-1 reduced the nicotine-induced dopamine release in the NAc in a dose-dependent manner. Nicotine-induced dopamine release was markedly diminished in tPA-deficient (tPA-/-) mice, and the defect of dopamine release in tPA-/- mice was restored by microinjection of either exogenous tPA or plasmin into the NAc. Nicotine increased tPA protein levels and promoted the release of tPA into the extracellular space in the NAc. Immunohistochemistry revealed that PAR1 immunoreactivity was localized to the nerve terminals positive for tyrosine hydroxylase in the NAc. Furthermore, we demonstrated that plasmin activated PAR1 and that nicotine-induced place preference and dopamine release were diminished in PAR1-deficient (PAR1-/-) mice. Targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches to the treatment of nicotine dependence.
authors.affiliation: Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.forename: Mina
authors.initials: M
authors.lastname: Ito
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nakamichi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kamei
authors.forename: Ayumi
authors.initials: A
authors.lastname: Fukakusa
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D004622:Embryo, Mammalian; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D011869:Radioligand Assay / Q000379:methods; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000502:physiology*; D012201:Reward; D018709:Statistics, Nonparametric; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
chemical_list: D018492:Dopamine Antagonists; D018722:Nicotinic Agonists; D044463:Receptor, PAR-1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009538:Nicotine; D010959:Tissue Plasminogen Activator; D000109:Acetylcholine; D004298:Dopamine