title: Involvement of tissue plasminogen activator "tPA" in ethanol-induced locomotor sensitization and conditioned-place preference.
abstract: Ethanol is one of the most abused drugs in the western societies. It is well established that mesolimbic dopaminergic neurons mediate the rewarding properties of ethanol. In our previous studies we have shown that the serine protease tissue plasminogen activator (tPA) is involved in the rewarding properties of morphine and amphetamine. In the current study, we investigated the role of tPA in ethanol-induced behavioral sensitization and conditioned-place preference (CPP). Ethanol treatment dose-dependently induced tPA enzymatic activity in the nucleus accumbens (NAc). In addition, ethanol-induced increase in tPA activity was completely inhibited by pre-treatment with the dopamine D1 and D2 receptor antagonists SCH23390 and raclopride respectively. Furthermore, ethanol-induced locomotor stimulation, behavioral sensitization and conditioned-place preference were enhanced following tPA over-expression in the NAc using a lentiviral vector. In contrast, tPA knock down in the NAc with specific shRNA blocked the rewarding properties of ethanol. The defect of locomotor stimulation in shRNA-injected mice was reversed by microinjections of exogenous recombinant tPA into the nucleus accumbens. Collectively, these results indicate, for the first time, that activation of tPA is effective in enhancing the rewarding effects of ethanol. Targeting the tissue plasminogen activator system would provide new therapeutic approaches to the treatment of alcoholism.
authors.affiliation: Department of Anatomy, Faculty of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates. amine.bahi@uaeu.ac.ae
authors.forename: Amine
authors.initials: A
authors.lastname: Bahi
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dreyer
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D020891:Raclopride / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; C534628:SCH 23390; D000431:Ethanol; D020891:Raclopride; D010959:Tissue Plasminogen Activator