Mongeau R, Weiss M, de Montigny C, Blier P
Neurobiological Psychiatry Unit, McGill University, Montreal, Quebec, Canada.
Neuropharmacology. 1998 Jul;37(7):905-18. doi: 10.1016/s0028-3908(98)00083-5.
The effect of milnacipran on the firing activity of dorsal raphe serotonin (5-HT) neurons and locus coeruleus norepineprine (NE) neurons was assessed using extracellular unitary recording in chloral hydrate anesthetized rats. A 2-day treatment with milnacipran (20 or 60 mg/kg/day, s.c.) markedly decreased the firing rate of NE neurons, and it remained reduced after a 7- or a 14-day treatment. Although the suppressant effect of the alpha2-adrenergic agonist clonidine on the firing rate of NE neurons was markedly reduced following long-term milnacipran (60 mg/kg/day x 14 days, s.c.), that of NE remained unchanged. The firing rate of 5-HT neurons was reduced following a 2-day treatment with milnacipran (20 mg/kg/day, s.c.), but there was a partial recovery after a 7-day treatment (20 mg/kg/day, s.c.) and a complete one after a 14-day treatment (20, 40 or 60 mg/kg/day, s.c.). The suppressant effect of 5-HT and of the 5-HT1A agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) on the firing rate of 5-HT neurons was also unaltered after milnacipran (60 mg/kg/day x 14 days, s.c.). The latter milnacipran treatment did not affect the uptake of [3H]5-HT but it inhibited that of [3H]NE by 30% in hippocampal slices. The NE system was thus investigated in an attempt to explain the effects of milnacipran on the firing activity of 5-HT neurons. Acute injection of milnacipran suppressed the firing activity of 5-HT neurons (with an ED50 of 5.7+/-1.5 mg/kg, i.v.), but not in NE-denervated rats. Furthermore, the inhibitory effect of clonidine on 5-HT neuron firing activity was markedly reduced by the long-term milnacipran treatment, whereas the inhibition of electrically evoked release of [3H]NE as well as that of [3H]5-HT produced by the alpha2-adrenoceptor agonist UK 14.304 from preloaded mesencephalic slices containing the dorsal raphe was unaltered. The latter results indicate that the alpha2-adrenergic autoreceptor and heteroreceptor were unaffected in the raphe area by milnacipran. In conclusion, milnacipran had profound effects on the function of 5-HT and NE neurons, and the mechanism by which 5-HT neurons regained their normal firing during milnacipran treatment appeared to implicate the NE system.
在水合氯醛麻醉的大鼠中，采用细胞外单位记录法评估了米那普明对中缝背核5-羟色胺（5-HT）能神经元和蓝斑去甲肾上腺素（NE）能神经元放电活动的影响。连续2天给予米那普明（20或60mg/kg/天，皮下注射）显著降低了NE能神经元的放电频率，且在7天或14天给药后仍维持在较低水平。虽然长期给予米那普明（60mg/kg/天×14天，皮下注射）后，α2-肾上腺素能激动剂可乐定对NE能神经元放电频率的抑制作用明显减弱，但NE能神经元的放电频率仍保持不变。给予米那普明（20mg/kg/天，皮下注射）2天后，5-HT能神经元的放电频率降低，但在7天给药（20mg/kg/天，皮下注射）后部分恢复，14天给药（20、40或60mg/kg/天，皮下注射）后完全恢复。米那普明（60mg/kg/天×14天，皮下注射）后，5-HT及5-HT1A激动剂8-OH-DPAT（8-羟基-2-（二正丙基氨基）四氢萘）对5-HT能神经元放电频率的抑制作用也未改变。后一种米那普明处理不影响海马切片中[3H]5-HT的摄取，但抑制了[3H]NE摄取的30%。因此，对NE系统进行了研究，以试图解释米那普明对5-HT能神经元放电活动的影响。急性注射米那普明可抑制5-HT能神经元的放电活动（静脉注射的半数有效剂量为5.7±1.5mg/kg），但在去甲肾上腺素能神经支配的大鼠中则无此作用。此外，长期给予米那普明可显著减弱可乐定对5-HT能神经元放电活动的抑制作用，而α2-肾上腺素能受体激动剂UK 14.304对预先加载含有中缝背核的中脑切片中[3H]NE以及[3H]5-HT电诱发释放的抑制作用未改变。后一结果表明，米那普明对中缝背核区域的α2-肾上腺素能自身受体和异源受体无影响。总之，米那普明对5-HT和NE能神经元的功能有深远影响，米那普明治疗期间5-HT能神经元恢复正常放电的机制似乎与NE系统有关。
