title: Knockdown of dopamine D₂ receptors in the nucleus accumbens core suppresses methamphetamine-induced behaviors and signal transduction in mice.
abstract: BACKGROUND
  Addictive drugs lead to reinforcing properties by increasing dopamine in the nucleus accumbens, which is composed of a core and shell regions. Neurons in the nucleus accumbens are divided into 2 subtypes based on the differential gene expression of the dopamine D₁ receptors and D₂ receptors.
  
  
  METHODS
  In the present study, we investigated the role of D₂ receptors in the nucleus accumbens core in behaviors and signal transduction induced by psychostimulant methamphetamine in mice that were microinjected with adeno-associated virus vectors containing a microRNA (miRNA) sequence for D₂ receptor (adeno-associated virus-miD2r vectors) in the nucleus accumbens core. The adeno-associated virus vectors containing a miRNA sequence for D₂ receptor-treated mice (miD₂r mice) were assessed at a reduction in D₂ receptor, but at no change in dopamine D₁ receptor, in the nucleus accumbens core compared with the adeno-associated virus-Mock vectors-treated mice (Mock mice).
  
  
  RESULTS
  miD₂r mice exhibited a reduction in hyperlocomotion that was induced by a single treatment with methamphetamine. The development of locomotor sensitization induced by repeated treatment with methamphetamine exhibited less extension in miD₂r mice. In a place conditioning paradigm, the preferred effects of methamphetamine were significantly weaker in miD₂r mice than in Mock mice. Furthermore, the single treatment with methamphetamine-induced phosphorylation of extracellular signal regulated kinase and cyclic adenosine monophosphate response element-binding protein in the nucleus accumbens core of miD₂r mice was decreased compared with that in Mock mice. Repeated treatment with methamphetamine-induced delta FBJ murine osteosarcoma viral oncogene homolog B accumulation in the nucleus accumbens core of miD₂r mice was also attenuated.
  
  
  CONCLUSIONS
  These findings suggest that a D₂ receptor-mediated neuronal pathway from the nucleus accumbens core plays an inhibitory role in the development of reinforcing properties.
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (Drs Miyamoto, Sato, and Nitta); Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan (Drs Iida and Muramatsu).
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, Japan (Drs Miyamoto, Sato, and Nitta); Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan (Drs Iida and Muramatsu).
authors.forename: Asako
authors.initials: A
authors.lastname: Iida
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (Drs Miyamoto, Sato, and Nitta); Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan (Drs Iida and Muramatsu).
authors.forename: Keiji
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (Drs Miyamoto, Sato, and Nitta); Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan (Drs Iida and Muramatsu).
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.affiliation: Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (Drs Miyamoto, Sato, and Nitta); Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan (Drs Iida and Muramatsu). nitta@pha.u-toyama.ac.jp.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
mesh_terms: D017109:Akathisia, Drug-Induced / Q000378:metabolism; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D000697:Central Nervous System Stimulants; D017362:Cyclic AMP Response Element-Binding Protein; C000600618:DRD2 protein, mouse; D035683:MicroRNAs; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D008694:Methamphetamine; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: adeno-associated virus vectors; dopamine D2 receptors; methamphetamine; nucleus accumbens