title: Chronic treatment with milnacipran reverses the impairment of synaptic plasticity induced by conditioned fear stress.
abstract: BACKGROUND
  Recent studies have focused on neural plasticity at the cellular and molecular levels in the etiology and treatment of stress-related disorders; however, there are no reports concerning modulation of synaptic plasticity in the hippocampus underlying therapeutic effects of antidepressants and/or anxiolytics.
  
  
  OBJECTIVE
  To elucidate the functional interaction between the stress-induced alteration of synaptic plasticity and therapeutic effects, we examined the anxiolytic mechanism(s) of milnacipran, focusing on modulation of long-term potentiation (LTP) in the hippocampal CA1 field.
  
  
  METHODS
  Rats that received footshock stimulation five times (intensity, 0.5 mA; duration, 2 s; shock interval, 30 s) for 5 days were treated with milnacipran (30 mg kg(-1), p.o.) or vehicle for 14 days. On the 15th day, rats were subjected to conditioned fear stress (CFS) to evaluate freezing behavior. Separate from the behavioral study, electrophysiological approach was performed to evaluate the synaptic efficacy under anesthesia.
  
  
  RESULTS
  Exposure to CFS suppressed LTP in the CA1 field. Chronic treatment with milnacipran (30 mg kg(-1), i.p. after 30 mg kg(-1) day(-1), p.o. x14 days), but not acute treatment (30 mg kg(-1), i.p. after vehicle 5 ml kg(-1) day(-1), p.o. x14 days), reduced freezing behavior and reversed the impairment of LTP induced by CFS.
  
  
  CONCLUSIONS
  The present data suggest that a correspondence exists between fear-related behavior and synaptic plasticity in the hippocampus. In other words, anxiolytic mechanism(s) of chronic treatment with milnacipran may be explained by reversal effects on the psychological stress-induced impairment of synaptic plasticity.
authors.affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Sapporo, 60-8638, Japan. mbird@med.hokudai.ac.jp
authors.forename: Machiko
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Kaori
authors.initials: K
authors.lastname: Tachibana
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togashi
authors.forename: Kazue
authors.initials: K
authors.lastname: Tahara
authors.forename: Taku
authors.initials: T
authors.lastname: Kojima
authors.forename: Taku
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshioka
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D003521:Cyclopropanes / Q000008:administration & dosage*; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D008297:Male; D000078764:Milnacipran; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013315:Stress, Psychological / Q000188:drug therapy* / Q000523:psychology; D013569:Synapses / Q000187:drug effects / Q000502:physiology
chemical_list: D003521:Cyclopropanes; D000078764:Milnacipran