Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone

Zoë A. Hughes, Kathryn R. Starr, Christopher J. Langmead, Matthew Hill, Gerd D. Bartoszyk, James J. Hagan, Derek N. Middlemiss, Lee A. Dawson

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Vilazodone has been reported to be an inhibitor of 5-hydoxytryptamine (5-HT) reuptake and a partial agonist at 5-HT1A receptors. Using [35S]GTPγS binding in rat hippocampal tissue, vilazodone was demonstrated to have an intrinsic activity comparable to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Vilazodone (1-10 mg/kg p.o.) dose-dependently displaced in vivo [3H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine) binding from rat cortex and hippocampus, indicating that vilazodone occupies 5-HT transporters in vivo. Using in vivo microdialysis, vilazodone (10 mg/kg p.o.) was demonstrated to cause a 2-fold increase in extracellular 5-HT but no change in noradrenaline or dopamine levels in frontal cortex of freely moving rats. In contrast, administration of 8-OH-DPAT (0.3 mg/kg s.c.), either alone or in combination with a serotonin specific reuptake inhibitor (SSRI; paroxetine, 3 mg/kg p.o.), produced no increase in cortical 5-HT whilst increasing noradrenaline and dopamine 2 and 4 fold, respectively. A 2-fold increase in extracellular 5-HT levels (but no change in noradrenaline or dopamine levels) was observed after combination of the 5-HT1A receptor antagonist, N-[2-[4-(2- methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide) (WAY-100635; 0.3 mg/kg s.c.) and paroxetine (3 mg/kg p.o.). In summary, vilazodone behaved as a high efficacy partial agonist at the rat hippocampal 5-HT1A receptors in vitro and occupied 5-HT transporters in vivo. In vivo vilazodone induced a selective increase in extracellular levels of 5-HT in the rat frontal cortex. This profile was similar to that seen with a 5-HT 1A receptor antagonist plus an SSRI but in contrast to 8-OH-DPAT either alone or in combination with paroxetine.

Original languageEnglish
Pages (from-to)49-57
Number of pages9
JournalEuropean Journal of Pharmacology
Issue number1-2
Publication statusPublished - 7 Mar 2005


  • 5-HT receptor
  • Frontal cortex
  • Microdialysis
  • N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxamide) (WAY-100635)
  • Paroxetine
  • Serotonin (5-hydroxytryptamine, 5-HT)

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