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

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 30 mg/kg, p.o. X 14 days) completely restored the suppression of the tong-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. X 14 days). These results suggest that milnacipran-induced restoration of LTP suppression is responsible for the enhancement of 5-HT neurotransmission, whichappears 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 rote 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.