Tachibana Kaori, Matsumoto Machiko, Koseki Hiroyo, Togashi Hiroko, Kojima Taku, Morimoto Yuji, Yoshioka Mitsuhiro
Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
J Psychopharmacol. 2006 Jul;20(4):562-9. doi: 10.1177/0269881106059694. Epub 2006 Jan 9.
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.
本研究旨在阐明血清素（5-HT）和去甲肾上腺素（NA）再摄取抑制剂（SNRI）米那普明重复给药对海马CA1区突触可塑性的影响，重点关注血清素能和去甲肾上腺素能系统之间的相互作用。米那普明重复给药（30mg/kg，腹腔注射，在30mg/kg口服给药14天后）完全恢复了单次米那普明给药（30mg/kg，腹腔注射）诱导的长时程增强（LTP）抑制。单次和重复给予米那普明可使海马细胞外NA增加至相似程度。单次给予米那普明可增加细胞外5-HT，重复给药往往会增强这种作用。选择性5-HT再摄取抑制剂（SSRI）氟伏沙明（30mg/kg，口服，14天）重复给药后未出现LTP恢复和5-HT水平升高。这些结果表明，米那普明诱导的LTP抑制恢复与5-HT神经传递增强有关，这似乎与去甲肾上腺素能神经元活动有关。此外，5-HT1A受体激动剂坦度螺酮诱导的LTP抑制被米那普明重复给药完全阻断，表明这种逆转作用可能是由于突触后5-HT1A受体的功能变化。综上所述，目前的数据表明，血清素能和去甲肾上腺素能机制之间的相互作用在米那普明重复给药引起的突触可塑性调节中起重要作用，这可能与SNRI对精神障碍的治疗作用有关。
