Chronic treatment with milnacipran reverses the impairment of synaptic plasticity induced by conditioned fear stress.
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.
Matsumoto
Machiko
M
Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Sapporo, 60-8638, Japan. mbird@med.hokudai.ac.jp
Tachibana
Kaori
K
Togashi
Hiroko
H
Tahara
Kazue
K
Kojima
Taku
T
Yamaguchi
Taku
T
Yoshioka
Mitsuhiro
M
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
D003521:Cyclopropanes; D000078764:Milnacipran