Basic and translational research on proteinase-activated receptors

Regulation of nicotine reward by the tissue plasminogen activator (tPA) - Plasmin system via proteinase-activated receptor 1

Taku Nagai, Toshitaka Nabeshima, Kiyofumi Yamada

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Nicotine, a primary component of tobacco, is one of the most abused drugs worldwide. Mesolimbic dopaminergic neurons mediate the rewarding effects of abused drugs, including nicotine. We show that the tissue plasminogen activator (tPA) - plasmin system regulates nicotine-induced reward and dopamine release in the nucleus accumbens (NAc) by activating proteinase-activated receptor 1 (PAR1). Nicotine-induced conditioned place preference and dopamine release in the NAc are diminished in tPA knockout (tPA-/-) mice. The defect of nicotine-induced dopamine release in tPA-/- mice is reversed by microinjection of either exogenous tPA or plasmin into the NAc. Acute nicotine treatment increases tPA protein levels and promoted the release of tPA into the extracellular space. The expression of PAR1 on dopaminergic neurons is evident and the activation of PAR1 by plasmin is demonstrated by assaying GTP-γS binding. Finally, nicotine-induced conditioned place preference and dopamine release are diminished in PAR1-/- mice. These findings suggest that targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches for the treatment of nicotine dependence.

Original languageEnglish
Pages (from-to)408-414
Number of pages7
JournalJournal of Pharmacological Sciences
Volume108
Issue number4
DOIs
Publication statusPublished - 01-12-2008

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Proteinase-Activated Receptors
PAR-1 Receptor
Translational Medical Research
Fibrinolysin
Tissue Plasminogen Activator
Nicotine
Reward
Dopamine
Nucleus Accumbens
Dopaminergic Neurons
Tobacco Use Disorder
Extracellular Space
Microinjections
Guanosine Triphosphate
Knockout Mice
Pharmaceutical Preparations
Tobacco
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Basic and translational research on proteinase-activated receptors: Regulation of nicotine reward by the tissue plasminogen activator (tPA) - Plasmin system via proteinase-activated receptor 1",
abstract = "Nicotine, a primary component of tobacco, is one of the most abused drugs worldwide. Mesolimbic dopaminergic neurons mediate the rewarding effects of abused drugs, including nicotine. We show that the tissue plasminogen activator (tPA) - plasmin system regulates nicotine-induced reward and dopamine release in the nucleus accumbens (NAc) by activating proteinase-activated receptor 1 (PAR1). Nicotine-induced conditioned place preference and dopamine release in the NAc are diminished in tPA knockout (tPA-/-) mice. The defect of nicotine-induced dopamine release in tPA-/- mice is reversed by microinjection of either exogenous tPA or plasmin into the NAc. Acute nicotine treatment increases tPA protein levels and promoted the release of tPA into the extracellular space. The expression of PAR1 on dopaminergic neurons is evident and the activation of PAR1 by plasmin is demonstrated by assaying GTP-γS binding. Finally, nicotine-induced conditioned place preference and dopamine release are diminished in PAR1-/- mice. These findings suggest that targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches for the treatment of nicotine dependence.",
author = "Taku Nagai and Toshitaka Nabeshima and Kiyofumi Yamada",
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N2 - Nicotine, a primary component of tobacco, is one of the most abused drugs worldwide. Mesolimbic dopaminergic neurons mediate the rewarding effects of abused drugs, including nicotine. We show that the tissue plasminogen activator (tPA) - plasmin system regulates nicotine-induced reward and dopamine release in the nucleus accumbens (NAc) by activating proteinase-activated receptor 1 (PAR1). Nicotine-induced conditioned place preference and dopamine release in the NAc are diminished in tPA knockout (tPA-/-) mice. The defect of nicotine-induced dopamine release in tPA-/- mice is reversed by microinjection of either exogenous tPA or plasmin into the NAc. Acute nicotine treatment increases tPA protein levels and promoted the release of tPA into the extracellular space. The expression of PAR1 on dopaminergic neurons is evident and the activation of PAR1 by plasmin is demonstrated by assaying GTP-γS binding. Finally, nicotine-induced conditioned place preference and dopamine release are diminished in PAR1-/- mice. These findings suggest that targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches for the treatment of nicotine dependence.

AB - Nicotine, a primary component of tobacco, is one of the most abused drugs worldwide. Mesolimbic dopaminergic neurons mediate the rewarding effects of abused drugs, including nicotine. We show that the tissue plasminogen activator (tPA) - plasmin system regulates nicotine-induced reward and dopamine release in the nucleus accumbens (NAc) by activating proteinase-activated receptor 1 (PAR1). Nicotine-induced conditioned place preference and dopamine release in the NAc are diminished in tPA knockout (tPA-/-) mice. The defect of nicotine-induced dopamine release in tPA-/- mice is reversed by microinjection of either exogenous tPA or plasmin into the NAc. Acute nicotine treatment increases tPA protein levels and promoted the release of tPA into the extracellular space. The expression of PAR1 on dopaminergic neurons is evident and the activation of PAR1 by plasmin is demonstrated by assaying GTP-γS binding. Finally, nicotine-induced conditioned place preference and dopamine release are diminished in PAR1-/- mice. These findings suggest that targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches for the treatment of nicotine dependence.

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