title: Electrophysiological evidence for rapid 5-HT₁A autoreceptor inhibition by vilazodone, a 5-HT₁A receptor partial agonist and 5-HT reuptake inhibitor.
abstract: This study examined the effect of vilazodone, a combined serotonin (5-HT) reuptake inhibitor and 5-HT(1A) receptor partial agonist, paroxetine and fluoxetine on the sensitivity of 5-HT(1A) autoreceptors of serotonergic dorsal raphe nucleus neurons in rats. These effects were assessed by determining the intravenous dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) required to suppress the basal firing rate of these neurons by 50% (ID₅₀) in anesthetized rats using in vivo electrophysiology. 5-HT uptake inhibition was determined by the ability of the compounds to reverse (±)-p-chloroamphetamine (PCA)-induced rat hypothalamic 5-HT depletion ex vivo. Acute vilazodone administration (0.63 and 2.1 µmol/kg, s.c.), compared with vehicle, significantly increased (2-3-fold) the ID₅₀ of 8-OH-DPAT at 4 h, but not 24h after administration. Subchronic administration (3 days) significantly increased the ID₅₀ value at 4 h (3-4-fold) and at 24 h (~2-fold). In contrast, paroxetine and fluoxetine at doses that were supramaximal for 5-HT uptake inhibition did not significantly alter the ID₅₀ value of 8-OH-DPAT after acute or subchronic administration. Vilazodone antagonized the action of PCA 3.5 h and 5 h after a single dose (ID₅₀ 1.49 and 0.46 µmol/kg, s.c., respectively), but was inactive 18 h post-administration, corroborating the electrophysiological results at 24 h following acute administration. The results are consistent with the concept of rapid and, following repeated treatment, prolonged inhibition of 5-HT(1A) autoreceptors by vilazodone. This effect could occur by either direct interaction with, or desensitization of, these receptors, an effect which cannot be ascribed to vilazodone's 5-HT reuptake inhibiting properties.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA. ashbyc@stjohns.edu.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: John H
authors.initials: JH
authors.lastname: Kehne
authors.forename: Gerd D
authors.initials: GD
authors.lastname: Bartoszyk
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Renda
authors.forename: Maria
authors.initials: M
authors.lastname: Athanasiou
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Pierz
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Seyfried
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology; D054333:Drug Partial Agonism; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D005277:Fenfluramine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000166:cytology / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D000069503:Vilazodone Hydrochloride; D010133:p-Chloroamphetamine / Q000494:pharmacology
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D001572:Benzofurans; D005277:Fenfluramine; D007211:Indoles; D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D000069503:Vilazodone Hydrochloride; D010133:p-Chloroamphetamine
keywords: 5-HT reuptake inhibitor; 5-HT(1A) receptor partial agonist; Antidepressant; In vivo electrophysiology; PCA model; Vilazodone