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Background  We have recently reported that serotonin 4  (5-HT 4 ) receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants.    Methodology/Principal Findings  We found that, in acute conditions, the 5-HT 4  agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphé Nucleus (DRN) cells selected for their high (>1.8 Hz) basal discharge. The co-administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT 4  agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT 1A  receptors, that was two to three times stronger when the 5-HT 4  agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine) was more effective to reduce time of immobility than the separate administration of each compound.    Conclusions/Significance  These findings strongly suggest that the adjunction of an SSRI to a 5-HT 4  agonist may help to optimize the fast-acting antidepressant efficacy of the latter.

Selective Serotonin Reuptake Inhibitors Potentiate the Rapid Antidepressant-Like Effects of Serotonin4 Receptor Agonists in the Rat