title: The role of tissue plasminogen activator in methamphetamine-related reward and sensitization.
abstract: In the central nervous system, tissue plasminogen activator (tPA) plays a role in synaptic plasticity and remodeling. Our recent study has suggested that tPA participates in the rewarding effects of morphine by regulating dopamine release. In this study, we investigated the role of tPA in methamphetamine (METH)-related reward and sensitization. Repeated METH treatment dose-dependently induced tPA mRNA expression in the frontal cortex, nucleus accumbens, striatum and hippocampus, whereas single METH treatment did not affect tPA mRNA expression in these brain areas. The METH-induced increase in tPA mRNA expression in the nucleus accumbens was completely inhibited by pre-treatment with R(+)-SCH23390 and raclopride, dopamine D1 and D2 receptor antagonists, respectively. In addition, repeated METH treatment increased tPA activity in the nucleus accumbens. There was no difference in METH-induced hyperlocomotion between wild-type and tPA-deficient (tPA-/-) mice. On the other hand, METH-induced conditioned place preference and behavioral sensitization after repeated METH treatment were significantly reduced in tPA-/- mice compared with wild-type mice. The defect of behavioral sensitization in tPA-/- mice was reversed by microinjections of exogenous tPA into the nucleus accumbens. Our findings suggest that tPA is involved in the rewarding effects as well as the sensitization of the locomotor-stimulating effect of METH.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Masako
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Mina
authors.initials: M
authors.lastname: Ito
authors.forename: Masanori
authors.initials: M
authors.lastname: Takayanagi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D019969:Amphetamine-Related Disorders / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D008694:Methamphetamine; D010959:Tissue Plasminogen Activator