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Electrophysiological and neurochemical characterization of the effect of repeated treatment with milnacipran on the rat serotonergic and noradrenergic systems

Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Machiko Matsumoto

Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Hiroyo Koseki

Department of Dental Anesthesiology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan

Hiroko Togashi

Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Taku Kojima

Yuji Morimoto

Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Mitsuhiro Yoshioka

Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

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 (30mg/kg, i.p. after 30mg/kg, p.o. 14 days) completely restored the suppression of the long-term potentiation (LTP) induced by single milnacipran treatment (30mg/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 (30mg/kg, p.o. 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-HT_1A 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-HT_1A 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

This version was published on July 1, 2006

Journal of Psychopharmacology, Vol. 20, No. 4, 562-569 (2006)
DOI: 10.1177/0269881106059694


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