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The Journal of Neuroscience, November 22, 2006, 26(47):12374-12383; doi:10.1523/JNEUROSCI.3139-06.2006
Behavioral/Systems/Cognitive
The Rewards of Nicotine: Regulation by Tissue Plasminogen Activator–Plasmin System through Protease Activated Receptor-1
Taku Nagai,1,2 * Mina Ito,1 * Noritaka Nakamichi,1 Hiroyuki Mizoguchi,1 Hiroyuki Kamei,1 Ayumi Fukakusa,1 Toshitaka Nabeshima,2 Kazuhiro Takuma,1 andKiyofumi Yamada1 1Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan, 2Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
Correspondence should be addressed to Kiyofumi Yamada, Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Email: kyamada{at}p.kanazawa-u.ac.jp
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.
Key words: dependence; behaviors; knock-out mice; protease; dopamine; nucleus accumbens
Received July 24, 2006; revised Oct. 23, 2006; accepted Oct. 25, 2006.
Correspondence should be addressed to Kiyofumi Yamada, Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Email: kyamada{at}p.kanazawa-u.ac.jp
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