title: Role of matrix metalloproteinase and tissue inhibitor of MMP in methamphetamine-induced behavioral sensitization and reward: implications for dopamine receptor down-regulation and dopamine release.
abstract: Matrix metalloproteinases (MMPs) and its inhibitors (TIMPs) function to remodel the pericellular environment. We have demonstrated that methamphetamine (METH)-induced behavioral sensitization and reward were markedly attenuated in MMP-2- and MMP-9 deficient [MMP-2-(-/-) and MMP-9-(-/-)] mice compared with those in wild-type mice, suggesting that METH-induced expression of MMP-2 and MMP-9 in the brain plays a role in the development of METH-induced sensitization and reward. In the present study, we investigated the changes in TIMP-2 expression in the brain after repeated METH treatment. Furthermore, we studied a role of MMP/TIMP system in METH-induced behavioral changes and dopamine neurotransmission. Repeated METH treatment induced behavioral sensitization, which was accompanied by an increase in TIMP-2 expression. Antisense TIMP-2 oligonucleotide (TIMP-AS) treatment enhanced the sensitization, which was associated with the potentiation of METH-induced dopamine release in the nucleus accumbens (NAc). On the other hand, MMP-2/-9 inhibitors blocked the METH-induced behavioral sensitization and conditioned place preference, a measure of the rewarding effect, and reduced the METH-increased dopamine release in the NAc. Dopamine receptor agonist-stimulated [(35)S]GTPgammaS binding was reduced in the frontal cortex of sensitized rats. TIMP-AS treatment potentiated, while MMP-2/-9 inhibitor attenuated, the reduction of dopamine D2 receptor agonist-stimulated [(35)S]GTPgammaS binding. Repeated METH treatment also reduced dopamine D2 receptor agonist-stimulated [(35)S]GTPgammaS binding in wild-type mice, but such changes were significantly attenuated in MMP-2-(-/-) and MMP-9-(-/-) mice. These results suggest that the MMP/TIMP system is involved in METH-induced behavioral sensitization and reward, by regulating dopamine release and receptor signaling.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Minae
authors.initials: M
authors.lastname: Niwa
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Banno
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, JapanLaboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa, JapanDepartment of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, JapanDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, JapanLaboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, JapanDepartment of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008297:Male; D020782:Matrix Metalloproteinases / Q000502:physiology*; D008694:Methamphetamine / Q000494:pharmacology*; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism; D012201:Reward; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015259:Dopamine Agents; D016376:Oligonucleotides, Antisense; D011480:Protease Inhibitors; D011954:Receptors, Dopamine; D019716:Tissue Inhibitor of Metalloproteinase-2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D008694:Methamphetamine; D020782:Matrix Metalloproteinases; D004298:Dopamine