title: Milnacipran remediates impulsive deficits in rats with lesions of the ventromedial prefrontal cortex.
abstract: BACKGROUND
  Deficits in impulse control are often observed in psychiatric disorders in which abnormalities of the prefrontal cortex are observed, including attention-deficit/hyperactivity disorder and bipolar disorder. We recently found that milnacipran, a serotonin/noradrenaline reuptake inhibitor, could suppress impulsive action in normal rats. However, whether milnacipran could suppress elevated impulsive action in rats with lesions of the ventromedial prefrontal cortex, which is functionally comparable with the human prefrontal cortex, remains unknown.
  
  
  METHODS
  Selective lesions of the ventromedial prefrontal cortex were made using quinolinic acid in rats previously trained on a 3-choice serial reaction time task. Sham rats received phosphate buffered saline. Following a period of recovery, milnacipran (0 or 10mg/kg/d × 14 days) was orally administered 60 minutes prior to testing on the 3-choice task. After 7 days of drug cessation, Western blotting, immunohistochemistry, electrophysiological analysis, and morphological analysis were conducted.
  
  
  RESULTS
  Lesions of the ventromedial prefrontal cortex induced impulsive deficits, and repeated milnacipran ameliorated the impulsive deficit both during the dosing period and after the cessation of the drug. Repeated milnacipran remediated the protein levels of mature brain-derived neurotrophic factor and postsynaptic density-95, dendritic spine density, and excitatory currents in the few surviving neurons in the ventromedial prefrontal cortex of ventromedial prefrontal cortex-lesioned rats.
  
  
  CONCLUSIONS
  The findings of this study suggest that milnacipran treatment could be a novel strategy for the treatment of psychiatric disorders that are associated with a lack of impulse control.
authors.affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Drs Tsutsui-Kimura, Yoshida, Ohmura, Izumi, and Yoshioka); Japan Society for the Promotion of Science, Tokyo, Japan (Dr Tsutsui-Kimura); Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (Dr Tsutsui-Kimura).
authors.forename: Iku
authors.initials: I
authors.lastname: Tsutsui-Kimura
authors.affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Drs Tsutsui-Kimura, Yoshida, Ohmura, Izumi, and Yoshioka); Japan Society for the Promotion of Science, Tokyo, Japan (Dr Tsutsui-Kimura); Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (Dr Tsutsui-Kimura).
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Drs Tsutsui-Kimura, Yoshida, Ohmura, Izumi, and Yoshioka); Japan Society for the Promotion of Science, Tokyo, Japan (Dr Tsutsui-Kimura); Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (Dr Tsutsui-Kimura). gwd0701@yahoo.co.jp.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ohmura
authors.affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Drs Tsutsui-Kimura, Yoshida, Ohmura, Izumi, and Yoshioka); Japan Society for the Promotion of Science, Tokyo, Japan (Dr Tsutsui-Kimura); Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (Dr Tsutsui-Kimura).
authors.forename: Takeshi
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Drs Tsutsui-Kimura, Yoshida, Ohmura, Izumi, and Yoshioka); Japan Society for the Promotion of Science, Tokyo, Japan (Dr Tsutsui-Kimura); Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (Dr Tsutsui-Kimura).
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshioka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001930:Brain Injuries / Q000139:chemically induced; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002755:Choice Behavior / Q000187:drug effects; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D007175:Impulsive Behavior / Q000187:drug effects*; D008297:Male; D000078764:Milnacipran; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009483:Neuropsychological Tests; D057907:Post-Synaptic Density / Q000187:drug effects / Q000473:pathology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003521:Cyclopropanes; D000078764:Milnacipran; D017378:Quinolinic Acid; D017367:Selective Serotonin Reuptake Inhibitors
keywords: BDNF; impulsive behavior; infralimbic cortex; inhibitory control; spinogenesis