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

Abstract

BackgroundWe have recently reported that serotonin4 (5-HT4) 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 FindingsWe found that, in acute conditions, the 5-HT4 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-HT4 agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT1A receptors, that was two to three times stronger when the 5-HT4 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/SignificanceThese findings strongly suggest that the adjunction of an SSRI to a 5-HT4 agonist may help to optimize the fast-acting antidepressant efficacy of the latter.

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

“…Indeed, the 5-HT 4 receptor agonist, RS67333, augmented the acute effect of paroxetine on extracellular 5-HT levels in rat ventral hippocampus, and after only 3 days of administration it increased basal hippocampal 5-HT levels (Licht et al, 2010). The coadministration of the SSRI citalopram and RS67333 strongly potentiated the antidepressant-like properties of the latter in several electrophysiological, molecular, and behavioral paradigms (Lucas et al, 2010).…”

“…It has been proposed that 5-HT 4 receptor agonists such as RS67333 may bring new hope for treating depression (Lucas, 2009;Lucas et al, 2005;Lucas and Debonnel, 2002;Lucas et al, 2010;Lucas et al, 2007). Indeed, administration of 5-HT 4 agonists induced similar molecular and behavioral changes as common antidepressants in rodents (Bockaert et al, 2008;Lucas et al, 2007;Pascual-Brazo et al, 2012).…”

Long-Term Adaptive Changes Induced by Antidepressants: From Conventional to Novel Therapies

“…Accordingly, subchronic (3 days) administration of RS67333, but not acute, increased basal 5-HT levels and decreased its metabolite levels 5-HIAA in the rat ventral hippocampus [82]. Furthermore, a 3-day co-administration of the SSRI citalopram and a 5-HT 4 receptor agonist, RS67333 or prucalopride, resulted in an increase of DRN 5-HT neuron mean firing activity, displaying a similar, or even slightly superior, firing amplitude obtained with each agonist alone [83]. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT 1A receptors, which was two to three times stronger when the 5-HT 4 receptor agonist was combined with citalopram [83].…”

“…Furthermore, a 3-day co-administration of the SSRI citalopram and a 5-HT 4 receptor agonist, RS67333 or prucalopride, resulted in an increase of DRN 5-HT neuron mean firing activity, displaying a similar, or even slightly superior, firing amplitude obtained with each agonist alone [83]. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT 1A receptors, which was two to three times stronger when the 5-HT 4 receptor agonist was combined with citalopram [83]. This suggests an important increase on the 5-HT neurotransmission following adjunction of an SSRI to a 5-HT 4 receptor agonist, clearly indicating a rapid AD-like potential of these agonists.…”

Serotonin (5-HT) release in the hippocampus following various conditions and treatments affecting 5-HT receptors has been studied in vivo mainly by the means of brain micro-dialysis: A review

“…Combination of 5-HT4 receptor agonists such as RS 67333 with SSRIs [i.e. citalopram, fluoxetine] result in rapid onset of a number of adaptations usually requiring chronic treatment with SSRIs alone [28]. They also regulate acetylcholine release [29] so that they may act as memory facilitators.…”