Selective Serotonin Reuptake Inhibitors Potentiate the Rapid Antidepressant-Like Effects of Serotonin4 Receptor Agonists in the Rat 英文参考文献.docVIP

SelectiveSerotoninReuptakeInhibitorsPotentiatethe RapidAntidepressant-LikeEffectsofSerotonin4Receptor AgonistsintheRat GuillaumeLucas1*,JennyDu1,ThomasRomeas1,OuissameMnie-Filali1,2,NasserHaddjeri2 ,Graciela Pin?eyro1,GuyDebonnel3{ 1DepartmentofPsychiatry,CentredeRechercheFernandSeguin,Universite′deMontre′al,Montre′al,Que′bec,Canada,2EACCNRS3006,ISPBUniversite′deLyon1,Faculty ofPharmacy,Lyon,France,3DepartmentofPsychiatry,Ba?timent deRechercheetdeFormation,Universite′ McGill,Montre′al,Que′bec, Canada Abstract Background:Wehaverecentlyreportedthatserotonin4(5-HT4)receptoragonistshaveapromisingpotentialasfast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventionalantidepressants. Methodology/Principal Findings: We found that, in acute conditions, the 5-HT4 agonist prucalopride was able to counteracttheinhibitory effectoftheselectiveserotoninreuptakeinhibitors(SSRI)fluvoxamineandcitalopramon5-HT neuron impulse flow, in Dorsal Raphe′ Nucleus (DRN) cells selected for their high (.1.8Hz) basal discharge. The co- administrationofbothprucaloprideandRS67333withcitalopramfor3dayselicitedanenhancementofDRN5-HTneuron average firing rate, very similar to what was observed with either 5-HT4 agonist alone. At the postsynaptic level, this translatedintothemanifestationofatonusonhippocampalpostsynaptic5-HT1A receptors,thatwastwotothreetimes strongerwhenthe5-HT4agonistwascombinedwithcitalopram.Similarly,co-administrationofcitalopramsynergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the ForcedSwimmingTest,thecombinationofRS67333withvariousSSRIs(fluvoxamine,citalopramandfluoxetine)wasmore effectivetoreducetimeofimmobilitythantheseparateadministrationofeachcompound. Conclusions/Significance:ThesefindingsstronglysuggestthattheadjunctionofanSSRItoa5-HT4agonistmayhelpto optimizethefast-actingantidepressantefficacyofthelatter.