López-Valdés H E, García-Colunga J
Centro de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Apartado Postal 1-1141, Juriquilla, Querétaro 76001, México.
Mol Psychiatry. 2001 Sep;6(5):511-9. doi: 10.1038/sj.mp.4000885.
A study was made of the effects of several monoamine-uptake inhibitors on membrane currents elicited by acetylcholine (ACh-currents) generated by rat neuronal alpha2beta4 and mouse muscle nicotinic acetylcholine receptors (AChRs) expressed in Xenopus laevis oocytes. For the two types of receptors the monoamine-uptake inhibitors reduced the ACh-currents albeit to different degrees. The order of inhibitory potency was norfluoxetine > clomipramine > indatraline > fluoxetine > imipramine > zimelidine > 6-nitro-quipazine > trazodone for neuronal alpha2beta4 AChRs, and norfluoxetine > fluoxetine > imipramine > clomipramine > indatraline > zimelidine > trazodone > 6-nitro-quipazine for muscle AChRs. Thus, the most potent inhibitor was norfluoxetine, whilst the weakest ones were trazodone, 6-nitro-quipazine and zimelidine. Effects of the tricyclic antidepressant imipramine were studied in more detail. Imipramine inhibited reversibly and non-competitively the ACh-current with a similar inhibiting potency for both neuronal alpha2beta4 and muscle AChRs. The half-inhibitory concentrations of imipramine were 3.65 +/- 0.30 microM for neuronal alpha2beta4 and 5.57 +/- 0.19 microM for muscle receptors. The corresponding Hill coefficients were 0.73 and 1.2 respectively. The inhibition of imipramine was slightly voltage-dependent, with electric distances of approximately 0.10 and approximately 0.12 for neuronal alpha2beta4 and muscle AChRs respectively. Moreover, imipramine accelerated the rate of decay of ACh- currents of both muscle and neuronal AChRs. The ACh-current inhibition was stronger when oocytes, expressing neuronal alpha2beta4 or muscle receptors, were preincubated with imipramine alone than when it was applied after the ACh-current had been generated, suggesting that imipramine acts also on non-activated or closed AChRs. We conclude that monoamine-uptake inhibitors reduce ACh-currents and that imipramine regulates reversibly and non- competitively neuronal alpha2beta4 and muscle AChRs through similar mechanisms, perhaps by interacting externally on a non-conducting state of the AChR and by blocking the open receptor-channel complex close to the vestibule of the channel. These studies may be important for understanding the regulation of AChRs as well as for understanding antidepressant- and side-effects of monoamine-uptake inhibitors.
研究了几种单胺摄取抑制剂对非洲爪蟾卵母细胞中表达的大鼠神经元α2β4和小鼠肌肉烟碱型乙酰胆碱受体（AChRs）所引发的乙酰胆碱电流（ACh电流）的影响。对于这两种类型的受体，单胺摄取抑制剂均能降低ACh电流，尽管程度不同。对于神经元α2β4 AChRs，抑制效力顺序为去甲氟西汀＞氯米帕明＞茚达曲林＞氟西汀＞丙咪嗪＞齐美利定＞6-硝基喹哌嗪＞曲唑酮；对于肌肉AChRs，抑制效力顺序为去甲氟西汀＞氟西汀＞丙咪嗪＞氯米帕明＞茚达曲林＞齐美利定＞曲唑酮＞6-硝基喹哌嗪。因此，最有效的抑制剂是去甲氟西汀，而最弱的是曲唑酮、6-硝基喹哌嗪和齐美利定。对三环类抗抑郁药丙咪嗪的作用进行了更详细的研究。丙咪嗪对神经元α2β4和肌肉AChRs的ACh电流具有可逆性和非竞争性抑制作用，且抑制效力相似。丙咪嗪对神经元α2β4的半抑制浓度为3.65±0.30微摩尔/升，对肌肉受体为5.57±0.19微摩尔/升。相应的希尔系数分别为0.73和1.2。丙咪嗪的抑制作用略有电压依赖性，神经元α2β4和肌肉AChRs的电距离分别约为0.10和约0.12。此外，丙咪嗪加速了肌肉和神经元AChRs的ACh电流的衰减速率。当单独用丙咪嗪预孵育表达神经元α2β4或肌肉受体的卵母细胞时，ACh电流的抑制作用比在产生ACh电流后应用丙咪嗪时更强，这表明丙咪嗪也作用于未激活或关闭的AChRs。我们得出结论，单胺摄取抑制剂可降低ACh电流，丙咪嗪通过类似机制对神经元α2β4和肌肉AChRs进行可逆性和非竞争性调节，可能是通过在AChR的非传导状态下进行外部相互作用，并通过在靠近通道前庭处阻断开放的受体-通道复合物。这些研究对于理解AChRs的调节以及理解单胺摄取抑制剂的抗抑郁作用和副作用可能具有重要意义。
