Electrophysiological and neurochemical characterization of the effect of
repeated treatment with milnacipran on the rat serotonergic and noradrenergic systems
Kaori Tachibana1,
Machiko Matsumoto2*,
Hiroyo Koseki3,
Hiroko Togashi2,
Taku Kojima1,
Yuji Morimoto1,
Mitsuhiro Yoshioka2
1 Department of Anesthesiology and Critical Care Medicine, Hokkaido
University Graduate School of Medicine, Sapporo, Japan
2 Department of Neuropharmacology, Hokkaido University Graduate School of
Medicine, Sapporo, Japan
3 Department of Dental Anesthesiology, Hokkaido University Graduate
School of Dental Medicine, Sapporo, Japan
* To whom correspondence should be addressed.
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Abstract |
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The present study was undertaken to elucidate the effects of repeated treatment
with milnacipran, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor (SNRI),
on the synaptic plasticity in the hippocampal CA1 field, focusing on the interaction
between the serotonergic and noradrenergic system. Repeated treatment with milnacipran
(30 mg/kg, i.p. after 30 mg/kg, p.o. x 14 days) completely restored the
suppression of the long-term potentiation (LTP) induced by single milnacipran treatment
(30 mg/kg, i.p.). Single and repeated milnacipran increased to a similar extent
extracellular NA in the hippocampus. Single milnacipran increased extracellular 5-HT and
this effect tended to be enhanced by repeated treatment. The restoration of LTP and
facilitation of the 5-HT level were not shown after repeated treatment with a selective
5-HT reuptake inhibitor (SSRI) fluvoxamine (30 mg/kg, p.o. x 14 days). These
results suggest that milnacipran-induced restoration of LTP suppression is responsible
for the enhancement of 5-HT neurotransmission, which appears to be associated with
noradrenergic neuronal activity. In addition, the 5-HT1A receptor agonist
tandospirone-induced suppression of LTP was completely blocked by repeated treatment
with milnacipran, indicating the possibility that this reversal effect is due to the
functional changes in postsynaptic 5-HT1A receptors. Taken together, the
present data suggest that the interaction between the serotonergic and noradrenergic
mechanism play an important role in the modulation of synaptic plasticity caused by
repeated treatment with milnacipran, which may be implicated in the therapeutic effects
of SNRI on psychiatric disorders.
Key Words:
milnacipran, fluvoxamine, SNRI, antidepressant, 5-HT1A receptors, noradrenaline, serotonin, LTP, hippocampus, CA1
