Role of melatonin, serotonin 2B, and serotonin 2C receptors in modulating the firing activity of rat dopamine neurons
Role of melatonin, serotonin 2B, and serotonin 2C receptors in modulating the firing activity of rat dopamine neurons
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DOI：
10.1177/0269881113510071
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发表时间：
2014-02-01
影响因子：
4.1
通讯作者：
Blier, Pierre
中科院分区：
文献类型：
--
作者：
Chenu, Franck;Shim, Stacey;Blier, Pierre
褪黑激素已被广泛用于治疗失眠，但在临床上缺乏抗抑郁作用。相反，阿戈美拉汀是一种有效的褪黑激素受体激动剂，是一种有效的抗抑郁药。然而，它也是一种有效的5-羟色胺2B（5-HT 2B）和5-羟色胺2C（5-HT 2C）受体拮抗剂。本研究的目的是调查在体内的影响，重复管理褪黑激素（40 mg/kg/天），5-HT 2C受体拮抗剂SB 242084（0.5 mg/kg/天），选择性5-HT 2B受体拮抗剂LY 266097（0.6 mg/kg/天）及其组合对腹侧被盖区（VTA）多巴胺（DA）、蓝斑（LC）去甲肾上腺素（NE），和中缝背核（DRN）5-羟色胺（5-HT）放电活动。每天两次给予褪黑激素增加自发活动的DA神经元的数量，但NE神经元的放电不变。长期给予褪黑激素和SB 242084本身对5-HT和DA神经元的放电率和爆发参数没有影响。然而，它们的组合只增加了自发活动的DA神经元的数量，而5-HT神经元的放电保持不变。LY 266097本身没有效果，但在先前的方案中加入LY 266097增加了DA神经元每分钟爆发的数量和爆发中出现的尖峰的百分比。总之，褪黑素受体激活以及5-HT 2C受体阻断的组合导致DA神经元的去抑制。当5-HT_2B受体也被阻断时，DA神经元的放电和爆发活动均增强，从而再现阿戈美拉汀的作用。
Melatonin has been widely used for the management of insomnia, but is devoid of antidepressant effect in the clinic. In contrast, agomelatine which is a potent melatonin receptor agonist is an effective antidepressant. It is, however, a potent serotonin 2B (5-HT2B) and serotonin 2C (5-HT2C) receptor antagonist as well. The present study was aimed at investigating the in vivo effects of repeated administration of melatonin (40 mg/kg/day), the 5-HT2C receptor antagonist SB 242084 (0.5 mg/kg/day), the selective 5-HT2B receptor antagonist LY 266097 (0.6 mg/kg/day) and their combination on ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) serotonin (5-HT) firing activity. Administration of melatonin twice daily increased the number of spontaneously active DA neurons but left the firing of NE neurons unaltered. Long-term administration of melatonin and SB 242084, by themselves, had no effect on the firing rate and burst parameters of 5-HT and DA neurons. Their combination, however, enhanced only the number of spontaneously active DA neurons, while leaving the firing of 5-HT neurons unchanged. The addition of LY 266097, which by itself is devoid of effect, to the previous regimen increased for DA neurons the number of bursts per minute and the percentage of spikes occurring in bursts. In conclusion, the combination of melatonin receptor activation as well as 5-HT2C receptor blockade resulted in a disinhibition of DA neurons. When 5-HT2B receptors were also blocked, the firing and the bursting activity of DA neurons were both enhanced, thus reproducing the effect of agomelatine.