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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 …