Abstract
Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin. In the present study, we investigated the role of the tPA-plasmin system in depolarization-evoked dopamine (DA) and acetylcholine (ACh) release in the nucleus accumbens (NAc) and hippocampus, respectively, of mice, by using in vivo microdialysis. Microinjection of either tPA or plasmin significantly potentiated 40 mM KCl-induced DA release without affecting basal DA levels. In contrast, plasminogen activator inhibitor-1 dose-dependently reduced 60 mM KCl-induced DA release. The 60 mM KCl-evoked DA release in the NAc was markedly diminished in tPA-deficient (tPA-/-) mice compared with wild-type mice, although basal DA levels did not differ between the two groups. Microinjections of either exogenous tPA (100 ng) or plasmin (100 ng) into the NAc of tPA-/-mice restored 60 mM KCl-induced DA release, as observed in wild-type mice. In contrast, there was no difference in either basal or 60 mM KCl-induced ACh release in the hippocampus between wild-type and tPA-/-mice. Our findings suggest that the tPA-plasmin system is involved in the regulation of depolarization-evoked DA release in the NAc.
Footnotes
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This study was supported in part by Grants-in Aid for Scientific Research (17790056) and for the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-Aid for Health Science Research from the Ministry of Health, Labor and Welfare of Japan, and grants from the Smoking Research Foundation, Japan, Public Health Research Foundation, Mitani Foundation, and Mochida Memorial Foundation for Medical and Pharmaceutical Research.
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M.I. and T.N. contributed equally to this work.
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ABBREVIATIONS: DA, dopamine; ACh, acetylcholine; BDNF, brain-derived neurotrophic factor; DA dopamine; NAc, nucleus accumbens; PAI-1, plasminogen activator inhibitor-1; PAR1, protease activated receptor-1; tPA, tissue plasminogen activator; aCSF, artificial cerebrospinal fluid; HPLC, high-performance liquid chromatography; ANOVA, analysis of variance; BSA, bovine serum albumin; tPA-/-, tissue plasminogen activator-deficient.
- Received January 10, 2006.
- Accepted August 14, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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