[Role of tissue plasminogen activator in the rewarding effect of nicotine]

Nicotine, a primary component of tobacco, is one of the most abused drugs worldwide. Approximately four million people die a year because of diseases associated with tobacco smoking. Nicotine rapidly reaches the brain through smoking and this leads to nicotine dependence. Drugs of abuse including nicotine acutely modulate the activity of mesolimbic dopaminergic neurons, projecting from the ventral tegmental area of the midbrain to the nucleus accumbens (NAc). Recently, it has been proposed that activity-dependent synaptic plasticity and remodeling of the mesolimbic dopaminergic system play a crucial role in the development of drug dependence. Tissue plasminogen activator (tPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. In our previous study, we have demonstrated that the tPA-plasmin system participates in the rewarding effect of morphine and methamphetamine. Here we show that the tPA-plasmin system regulates nicotine-induced reward and dopamine release. In vivo microdialysis revealed that microinjection of either tPA or plasmin into the 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 protease activated receptor-1 (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. Our findings suggest that targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches to the treatment of nicotine dependence.