title: Mechanism of action of the bimodal antidepressant vilazodone: evidence for serotonin1A-receptor-mediated auto-augmentation of extracellular serotonin output.
abstract: BACKGROUND
  The 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.
  
  
  OBJECTIVE
  The role of the 5-HT1A receptor with respect to the regulation of 5-HT output in the mechanism of action of vilazodone.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Vilazodone-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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Department of CNS Research, Biomedical Research, Merck KGaA, Frankfurter Strasse 250, 64293, Darmstadt, Germany, Christoph.vanAmsterdam@merckgroup.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: van Amsterdam
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Seyfried
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005110:Extracellular Space / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D017374:Paroxetine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D000069503:Vilazodone Hydrochloride
chemical_list: D006916:5-Hydroxytryptophan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000928:Antidepressive Agents; D001572:Benzofurans; D015283:Citalopram; D005473:Fluoxetine; D007211:Indoles; D017374:Paroxetine; D010879:Piperazines; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D000069503:Vilazodone Hydrochloride; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide