title: Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone.
abstract: Vilazodone has been reported to be an inhibitor of 5-hydoxytryptamine (5-HT) reuptake and a partial agonist at 5-HT1A receptors. Using [35S]GTPgammaS 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-HT(1A) 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-HT1A receptor antagonist plus an SSRI but in contrast to 8-OH-DPAT either alone or in combination with paroxetine.
authors.affiliation: Neuropharmacology Research, Psychiatry CEDD, Glaxo Smith Kline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.
authors.forename: Zoë A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Starr
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Langmead
authors.forename: Matthew
authors.initials: M
authors.lastname: Hill
authors.forename: Gerd D
authors.initials: GD
authors.lastname: Bartoszyk
authors.forename: James J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: Derek N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001596:Benzylamines / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000737:chemistry / Q000187:drug effects; D005625:Frontal Lobe / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism; D017374:Paroxetine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D010881:Piperidones / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D013997:Time Factors; D014316:Tritium; D000069503:Vilazodone Hydrochloride
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D001572:Benzofurans; D001596:Benzylamines; D004298:Dopamine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007211:Indoles; D009638:Norepinephrine; D017374:Paroxetine; D010879:Piperazines; D010881:Piperidones; D011725:Pyridines; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D013141:Spiro Compounds; D013462:Sulfur Radioisotopes; D014316:Tritium; D000069503:Vilazodone Hydrochloride; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; C108518:SB 22489G; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide