title: A 5-HT3 receptor antagonist potentiates the behavioral, neurochemical and electrophysiological actions of an SSRI antidepressant.
abstract: More effective treatments for major depression are needed. We studied if the selective 5-HT3 receptor antagonist ondansetron can potentiate the antidepressant potential of the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine using behavioral, neurochemical and electrophysiological methods. Flinders Sensitive Line (FSL) rats, treated with ondansetron, and/or a sub-effective dose of paroxetine, were assessed in the forced swim test. The effects of an acute intravenous administration of each compound alone and in combination were evaluated with respect to 5-HT neuronal firing rate in the dorsal raphe nucleus (DRN). Effects of s.c. administration of the compounds alone and in combination on extracellular levels of 5-HT were assessed in the ventral hippocampus of freely moving rats by microdialysis. The results showed that ondansetron enhanced the antidepressant activity of paroxetine in the forced swim test. It partially prevented the suppressant effect of paroxetine on DRN 5-HT neuronal firing and enhanced the paroxetine-induced increase of hippocampal extracellular 5-HT release. These findings indicate that 5-HT3 receptor blockade potentiates the antidepressant effects of SSRIs. Since both paroxetine and ondansetron are used clinically, it might be possible to validate this augmentation strategy in depressed patients.
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, Université de Lyon, Université Lyon I F-69008, France.
authors.forename: C
authors.initials: C
authors.lastname: Bétry
authors.affiliation: Department of Psychiatry, Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599-7178, USA.
authors.forename: D
authors.initials: D
authors.lastname: Overstreet
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, Université de Lyon, Université Lyon I F-69008, France. Electronic address: nasser.haddjeri@inserm.fr.
authors.forename: N
authors.initials: N
authors.lastname: Haddjeri
authors.affiliation: Neuropharmacological Research, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Pehrson
authors.affiliation: Discovery DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Neuropharmacological Research, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Synaptic Transmission In Vivo, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Mørk
mesh_terms: D000818:Animals; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D008297:Male; D017551:Microdialysis; D017294:Ondansetron / Q000494:pharmacology*; D017374:Paroxetine / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis / Q000502:physiology; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000819:agonists*
chemical_list: D017294:Ondansetron; D017374:Paroxetine; D012701:Serotonin; D058831:Serotonin 5-HT3 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 5-HT(3) receptor; Antidepressants; Major depressive disorder; Ondansetron; Paroxetine