[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.