Christoph van Amsterdam1, Christoph A Seyfried. 1. Department of CNS Research, Biomedical Research, Merck KGaA, Frankfurter Strasse 250, 64293, Darmstadt, Germany, Christoph.vanAmsterdam@merckgroup.com.
Abstract
RATIONALE: 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. METHOD: 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.
RATIONALE: 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. METHOD: 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: L Johansson; D Sohn; S O Thorberg; D M Jackson; D Kelder; L G Larsson; L Rényi; S B Ross; C Wallsten; H Eriksson; P S Hu; E Jerning; N Mohell; A Westlind-Danielsson Journal: J Pharmacol Exp Ther Date: 1997-10 Impact factor: 4.030
Authors: Ronald S Oosting; Johnny S Chan; Berend Olivier; Pradeep Banerjee; Yong Kee Choi; Frank Tarazi Journal: Psychopharmacology (Berl) Date: 2016-01-13 Impact factor: 4.530