ArticlePsychopharmacology2014
Mechanism of action of the bimodal antidepressant vilazodone: evidence for serotonin1A-receptor-mediated auto-augmentation of extracellular serotonin output.
Article in Psychopharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed, 18 citations in OpenAlex.
- The faster-onset antidepressant effects of hypidone hydrochloride (YL-0919).Metabolic brain disease · 2019Article
- Differential effects of vilazodone versus citalopram and paroxetine on sexual behaviors and serotonin transporter and receptors in male rats.Psychopharmacology · 2016Article
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
rationaleThe recently approved antidepressant vilazodone, a serotonin (5-HT)1A receptor partial agonist/selective 5-HT reuptake inhibitor offers new possibilities to study the underlying mechanisms of depression pharmacotherapy and of 5-HT augmenting antidepressants.
objectiveThe role of the 5-HT1A receptor with respect to the regulation of 5-HT output in the mechanism of action of vilazodone.
methodWe measured 5-HT levels in two subregions of the rat prefrontal cortex by microdialysis, and 5-hydroxytryptophan (5-HTP) accumulation and tissue 5-HT concentrations ex vivo.
resultsVilazodone-induced maximal 5-HT levels were similar in the medial and the lateral cortex and were up to sixfold higher than those induced by paroxetine, citalopram, or fluoxetine tested in parallel. Depolarization/autoreceptor-insensitive 5-HT release by vilazodone could be excluded. The citalopram (1 μM, locally infused)-induced increase of 5-HT was further increased by vilazodone (1 mg/kg i.p.), but not by citalopram (10 mg/kg i.p.). Unlike fluoxetine, vilazodone-induced extracellular 5-HT output was not potentiated by cotreatment with the 5-HT1A receptor blocker N-[2-(4-{2-methoxyphenyl}-1-piperazinyl)-ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635). In contrast to fluoxetine, vilazodone exhibited intrinsic 5-HT1A agonist activity: it reduced, similar to (±)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT), 5-HTP accumulation in striatum and n. raphe of reserpinized rats. Hence, vilazodone's agonistic actions must be 5-HT1A receptor-related since endogenous 5-HT is lacking in the reserpine-depleted animal.
conclusionsIn spite of high intrinsic 5-HT1A activity in reserpinized rats, the net effect of vilazodone at release-regulating 5-HT1A autoreceptors must be inhibitory, leading to markedly increased 5-HT output. Another possibility is that vilazodone rapidly desensitizes autoinhibitory 5-HT1A receptors by an unknown mechanism.
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