RT Journal Article
SR Electronic
T1 The Rewards of Nicotine: Regulation by Tissue Plasminogen Activator–Plasmin System through Protease Activated Receptor-1
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12374
OP 12383
DO 10.1523/JNEUROSCI.3139-06.2006
VO 26
IS 47
A1 Taku Nagai
A1 Mina Ito
A1 Noritaka Nakamichi
A1 Hiroyuki Mizoguchi
A1 Hiroyuki Kamei
A1 Ayumi Fukakusa
A1 Toshitaka Nabeshima
A1 Kazuhiro Takuma
A1 Kiyofumi Yamada
YR 2006
UL http://www.jneurosci.org/content/26/47/12374.abstract
AB 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.