Current antidepressants are clinically effective only after several weeks of administration. Because our previous studies indicated that both acute and sustained stimulation of serotonin4 (5-HT4) receptors facilitate central 5-HT activity, we assessed the ability of 5-HT4 agonists to induce antidepressant-like effects in the rat brain within a short (3 days) time-frame.

We found that 5-HT4 agonists reduce immobility in the Forced Swimming Test, displaying an antidepressant potential. Moreover, a 3-day regimen with such compounds modify rat brain parameters considered as key markers of antidepressant action, but observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT1A autoreceptors, increased tonus on hippocampal postsynaptic 5-HT1A receptors, enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. A 3-day regimen with the 5-HT4 agonist RS 67333 was also sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy, and the diminution of sucrose intake consecutive to a chronic mild stress. Moreover, the concomitant administration of a 5-HT4 receptor agonists with a classical antidepressant (SSRI) potentiated the amplitude of these effects, without altering the rapidity of action of the former.

These findings point out 5-HT4 receptor agonists as a putative new class of antidepressants, with a rapid onset of action.