Millan Mark John
Institut de Recherches Servier, Croissy-sur-Seine, France.
Therapie. 2005 Sep-Oct;60(5):441-60. doi: 10.2515/therapie:2005065.
Serotonin (5-HT)2C receptors play an important role in the modulation of monoaminergic transmission, mood, motor behaviour, appetite and endocrine secretion, and alterations in their functional status have been detected in anxiodepressive states. Further, 5-HT2C sites are involved in the actions of several classes of antidepressant. At the onset of treatment, indirect activation of 5-HT2C receptors participates in the anxiogenic effects of selective 5-HT reuptake inhibitors (SSRIs) as well as their inhibition of sleep, sexual behaviour and appetite. Conversely, progressive down-regulation of 5-HT2C receptors parallels the gradual onset of clinical efficacy of SSRIs. Other antidepressants, such as nefazodone or mirtazapine, act as direct antagonists of 5-HT2C receptors. These observations underpin interest in 5-HT2C receptor blockade as a strategy for treating depressive and anxious states. This notion is supported by findings that 5-HT2C receptor antagonists stimulate dopaminergic and adrenergic pathways, exert antidepressant and anxiolytic actions in behavioural paradigms, and favour sleep and sexual function. In addition to selective antagonists, novel strategies for exploitation of 5-HT2C receptors embrace inverse agonists, allosteric modulators, ligands of homo/heterodimers, modulators of interactions with 'postsynaptic proteins', dual melatonin agonists/5-HT2C receptor antagonists and mixed 5-HT2C/alpha2-adrenergic antagonists. Intriguingly, there is evidence that stimulation of regionally discrete populations of 5-HT2C receptors is effective in certain behavioural models of antidepressant activity, and promotes neurogenesis in the hippocampus. This article explains how these ostensibly paradoxical actions of 5-HT2C antagonists and agonists can be reconciled and discusses both established and innovative strategies for the exploitation of 5-HT2C receptors in the improved management of depressed and anxious states.
血清素（5-羟色胺，5-HT）2C受体在单胺能传递、情绪、运动行为、食欲和内分泌分泌的调节中发挥重要作用，并且在焦虑抑郁状态下已检测到其功能状态的改变。此外，5-HT2C位点参与了几类抗抑郁药的作用。在治疗开始时，5-HT2C受体的间接激活参与了选择性5-羟色胺再摄取抑制剂（SSRI）的致焦虑作用以及它们对睡眠、性行为和食欲的抑制。相反，5-HT2C受体的逐渐下调与SSRI临床疗效的逐渐显现平行。其他抗抑郁药，如奈法唑酮或米氮平，作为5-HT2C受体的直接拮抗剂起作用。这些观察结果支持了将5-HT2C受体阻断作为治疗抑郁和焦虑状态的策略的兴趣。这一观点得到了以下发现的支持：5-HT2C受体拮抗剂刺激多巴胺能和肾上腺素能途径，在行为范式中发挥抗抑郁和抗焦虑作用，并有利于睡眠和性功能。除了选择性拮抗剂外，开发5-HT2C受体的新策略还包括反向激动剂、变构调节剂、同型/异型二聚体配体、与“突触后蛋白”相互作用的调节剂、双重褪黑素激动剂/5-HT2C受体拮抗剂以及5-HT2C/α2-肾上腺素能混合拮抗剂。有趣的是，有证据表明，刺激区域离散的5-HT2C受体群体在某些抗抑郁活性行为模型中是有效的，并能促进海马体中的神经发生。本文解释了5-HT2C拮抗剂和激动剂这些表面上矛盾的作用如何能够协调一致，并讨论了在改善抑郁和焦虑状态管理中开发5-HT2C受体的既定策略和创新策略。
