[Regulation by tissue plasminogen activator of rewarding effects of drugs of abuse].
Drugs of abuse acutely modulate the activity of mesolimbic dopaminergic neurons, projecting from the ventral tegmental area of the midbrain to the nucleus accumbens (NAc). Tissue plasminogen activator (tPA) is a serine protease that catalyzes the conversion of plasminogen (plg) to plasmin. Here we show that this protease system participates in the rewarding effects of morphine, methamphetamine (METH) and nicotine. A single morphine treatment induces tPA mRNA and protein expression in the NAc. Morphine-induced conditioned place preference and hyperlocomotion are significantly reduced in tPA-deficient (tPA-/-) and plg-deficient (plg-/-) mice, being accompanied by a loss of morphine-induced dopamine release in the NAc. Repeated METH treatment also induces tPA mRNA expression in the NAc. METH-induced conditioned place preference and behavioral sensitization after repeated METH treatment are significantly reduced in tPA-/- mice compared with those in wild-type mice. Finally, we show that the tPA-plasmin system regulates nicotine-induced reward and dopamine release by activating protease activated receptor-1 (PAR1). Nicotine-induced dopamine release is markedly diminished in tPA-/- mice. Furthermore, plasmin activates PAR1 and nicotine-induced conditioned place preference and dopamine release are diminished in PAR1-deficient mice. Our findings suggest that targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches to the treatment of drug dependence.
Nagai
Taku
T
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8560 Japan.
Takuma
Kazuhiro
K
Nabeshima
Toshitaka
T
Yamada
Kiyofumi
K
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D005341:Fibrinolysin / Q000502:physiology; D008694:Methamphetamine / Q000009:adverse effects; D051379:Mice; D009020:Morphine / Q000009:adverse effects; D009538:Nicotine / Q000009:adverse effects; D009714:Nucleus Accumbens / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism / Q000502:physiology; D019966:Substance-Related Disorders / Q000209:etiology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000502:physiology*
D044463:Receptor, PAR-1; D008694:Methamphetamine; D009538:Nicotine; D009020:Morphine; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D004298:Dopamine