title: Overexpression of Shati/Nat8l, an N-acetyltransferase, in the nucleus accumbens attenuates the response to methamphetamine via activation of group II mGluRs in mice.
abstract: A novel N-acetyltransferase, Shati/Nat8l, was identified in the nucleus accumbens (NAc) of mice with methamphetamine (METH) treatment. Previously we reported that suppression of Shati/Nat8l enhanced METH-induced behavioral alterations via dopaminergic neuronal regulation. However, the physiological mechanisms of Shati/Nat8l on the dopaminergic system in the brain are unclear. In this study, we injected adeno-associated virus (AAV) vector containing Shati/Nat8l into the NAc or dorsal striatum (dS) of mice, to increase Shati/Nat8l expression. Overexpression of Shati/Nat8l in the NAc, but not in the dS, attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference in mice. Moreover, the Shati/Nat8l overexpression in the NAc attenuated the elevation of extracellular dopamine levels induced by METH in in vivo microdialysis experiments. These behavioral and neurochemical alterations due to Shati/Nat8l overexpression in the NAc were inhibited by treatment with selective group II metabotropic glutamate receptor type 2 and 3 (mGluR2/3) antagonist LY341495. In the AAV vector-injected NAc, the tissue contents of both N-acetylaspartate and N-acetylaspartylglutamate (NAAG), endogenous mGluR3 agonist, were elevated. The injection of peptidase inhibitor of NAAG or the perfusion of NAAG itself reduced the basal levels of extracellular dopamine in the NAc of naive mice. These results indicate that Shati/Nat8l in the NAc, but not in the dS, plays an important suppressive role in the behavioral responses to METH by controlling the dopaminergic system via activation of group II mGluRs.
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences,University of Toyama,Toyama 930-0194,Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences,University of Toyama,Toyama 930-0194,Japan.
authors.forename: Yudai
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences,University of Toyama,Toyama 930-0194,Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iegaki
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences,University of Toyama,Toyama 930-0194,Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sumi
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences,University of Toyama,Toyama 930-0194,Japan.
authors.forename: Kequan
authors.initials: K
authors.lastname: Fu
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences,University of Toyama,Toyama 930-0194,Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy,Nagoya University Graduate School of Medicine,Nagoya 466-8560,Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Furukawa-Hibi
authors.affiliation: Division of Neurology, Department of Medicine,Jichi Medical University,Shimotsuke 329-0498,Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Muramatsu
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy,Nagoya University Graduate School of Medicine,Nagoya 466-8560,Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences,University of Toyama,Toyama 930-0194,Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Uno
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences,University of Toyama,Toyama 930-0194,Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D004151:Dipeptides; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C027172:isospaglumic acid; D001224:Aspartic Acid; D008694:Methamphetamine; C000179:N-acetylaspartate; D000123:Acetyltransferases; C521704:Shati protein, mouse; D004298:Dopamine