Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin₄ (5-HT₄) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2–3 week treatments with classical molecules: desensitization of 5-HT_1A autoreceptors, increased tonus on hippocampal postsynaptic 5-HT_1A receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT₄ agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT₄ receptor agonists as a putative class of antidepressants with a rapid onset of action.