UMR-S839 INSERM, Paris, France.
Mol Psychiatry. 2012 Feb;17(2):154-63. doi: 10.1038/mp.2011.159. Epub 2011 Dec 13.
The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking the serotonin transporter and rely on long-term adaptations of pre- and post-synaptic receptors. We show here that long-term behavioral and neurogenic SSRI effects are abolished after either genetic or pharmacological inactivation of 5-HT(2B) receptors. Conversely, direct agonist stimulation of 5-HT(2B) receptors induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (i) this receptor is expressed by raphe serotonergic neurons, (ii) the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT(2B) receptors and (iii) a selective 5-HT(2B) agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT(2B) receptors. The 5-HT(2B) receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT(2B) receptor should be considered as a new tractable target in the combat against depression.
5-羟色胺 2B 受体正向调节 5-羟色胺能神经元活动并参与选择性 5-羟色胺再摄取抑制剂的抗抑郁作用
选择性 5-羟色胺再摄取抑制剂（SSRIs）抗抑郁药的治疗效果最初是通过阻断 5-羟色胺转运体而产生的，并依赖于突触前和突触后受体的长期适应性变化。我们在这里表明，5-羟色胺 2B（5-HT2B）受体的基因或药理学失活会消除长期的行为和神经发生的 SSRI 作用。相反，5-HT2B 受体的直接激动剂刺激会在行为和神经发生测定中诱导出类似于 SSRI 的反应。此外，（i）该受体由中缝 5-羟色胺能神经元表达，（ii）在缺乏功能性 5-HT2B 受体的情况下，SSRI 诱导的海马细胞外 5-羟色胺浓度增加会大大减少，以及（iii）选择性 5-HT2B 激动剂模拟 SSRI 反应，这些观察结果支持 5-HT2B 受体对 5-羟色胺能神经元的正向调节。因此，5-HT2B 受体似乎正向调节 5-羟色胺能活性，并作为 SSRIs 治疗作用的必要条件。因此，5-HT2B 受体应该被视为对抗抑郁症的一个新的可治疗靶点。
