5-[HT.sub.2B] receptors are required for serotonin-selective antidepressant actions

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.sub.2B] receptors. Conversely, direct agonist stimulation of 5-[HT.sub.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.sub.2B] receptors and (iii) a selective 5-[HT.sub.2B] agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-[HT.sub.2B] receptors. The 5-[HT.sub.2B] receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-[HT.sub.2B] receptor should be considered as a new tractable target in the combat against depression. Molecular Psychiatry (2012) 17,154-163; doi: 10.1038/mp.2011.159; published online 13 December 2011 Keywords: serotonin levels; 5-[HT.sub.2B] receptors; antidepressants; neurogenesis