title: Role of the NMDA receptor GluN2D subunit in the expression of ketamine-induced behavioral sensitization and region-specific activation of neuronal nitric oxide synthase.
abstract: The present study aimed to investigate the involvement of the NMDA receptor (NMDAR) and/or nitric oxide (NO) pathway in ketamine-induced behavioral sensitization. Mice received repeated subcutaneous administration of ketamine (25mg/kg), once daily or once weekly for a total of five doses. Even three administrations of ketamine, daily or weekly, induced a rapid increase in locomotor activity in wild-type (WT), but not in GluN2D knockout (GluN2D-KO) mice. Furthermore, for WT mice receiving daily ketamine, elevated locomotor activity was maintained after a 1-month withdrawal period; however, this was not the case when ketamine was administered weekly. The effect of acute ketamine on nNOS activities was estimated with nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) histochemistry. Ketamine rapidly increased the number of NADPH-d activated cells and strongly stained dendrites in the dorsal striatum and prefrontal cortex of WT mice, but not GluN2D-KO mice. These results suggest that ketamine-induced locomotor sensitization and nNOS activation in the frontal cortex-striatum neuronal circuit are positively correlated and that the NMDAR GluN2D subunit plays an important role in the acquisition and maintenance of ketamine-induced behavioral sensitization.
authors.affiliation: Laboratory of Molecular Psychopharmacology, Graduate School of Nanobiosciences, Yokohama City University, 22-2 Seto, Kanazawa-Ku, Yokohama 236-0027, Japan. Electronic address: yamamoto@yokohama-cu.ac.jp.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Molecular Psychopharmacology, Graduate School of Nanobiosciences, Yokohama City University, 22-2 Seto, Kanazawa-Ku, Yokohama 236-0027, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Laboratory of Molecular Psychopharmacology, Graduate School of Nanobiosciences, Yokohama City University, 22-2 Seto, Kanazawa-Ku, Yokohama 236-0027, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of Molecular Psychopharmacology, Graduate School of Nanobiosciences, Yokohama City University, 22-2 Seto, Kanazawa-Ku, Yokohama 236-0027, Japan.
authors.forename: Maaya
authors.initials: M
authors.lastname: Matsuzawa
authors.affiliation: Ritsumeikan University Research Organization of Science and Technology, Kusatsu, Shiga 525-8577, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-Ku, Tokyo 156-8506, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-Ku, Tokyo 156-8506, Japan.
authors.forename: Hideko
authors.initials: H
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009249:NADP / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D009928:Organ Specificity; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: C464436:NR2D NMDA receptor; D021122:Protein Subunits; D011619:Psychotropic Drugs; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D009249:NADP; D007649:Ketamine; D052248:Nitric Oxide Synthase Type I
keywords: GluN2D; Ketamine; Knockout; Neuronal nitric oxide synthase; Sensitization