The rewards of nicotine: Regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1
The rewards of nicotine: Regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1
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DOI：
10.1523/jneurosci.3139-06.2006
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发表时间：
2006-11-22
影响因子：
5.3
通讯作者：
Yamada, Kiyofumi
中科院分区：
文献类型：
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作者：
Nagai, Taku;Ito, Mina;Yamada, Kiyofumi
尼古丁是烟草的主要成分，是世界上滥用最严重的药物之一。每年约有400万人死于与吸烟有关的疾病。中脑边缘多巴胺能神经元介导包括尼古丁在内的滥用药物的奖赏效应。在这里，我们发现组织纤溶酶原激活物(TPA)-纤溶酶系统通过激活蛋白酶激活受体-1(PAR1)来调节尼古丁诱导的奖赏和多巴胺的释放。在体微透析显示，伏核(NAC)内微量注射tPA或纤溶酶可显着增强伏隔核(NAC)的多巴胺释放，而纤溶酶原激活物抑制物-1(PAI-1)则呈剂量依赖性地抑制尼古丁诱导的NAC的多巴胺释放。TPA(-/-)缺陷型(tPA(-/-))小鼠烟碱诱导的多巴胺释放明显减少，外源性tPA或纤溶酶可恢复tPA(-)/(-)小鼠的多巴胺释放缺陷。尼古丁使NAC内tPA蛋白水平升高，并促进tPA释放到细胞外间隙。免疫组织化学显示PAR1免疫反应定位于NAC内酪氨酸羟化酶阳性的神经末梢。此外，我们还证明了纤溶酶激活了PAR1，尼古丁诱导的位置偏爱和多巴胺释放在PAR1缺陷(PAR1(-)/(-))小鼠中被减弱。靶向tPA-纤溶酶-PAR1系统将为尼古丁依赖的治疗提供新的治疗方法。
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.