Subchronic vortioxetine treatment -but not escitalopram- enhances pyramidal neuron activity in the rat prefrontal cortex.
Vortioxetine (VOR) is a multimodal antidepressant drug. VOR is a 5-HT3-R, 5-HT7-R and 5-HT1D-R antagonist, 5-HT1B-R partial agonist, 5-HT1A-R agonist, and serotonin transporter (SERT) inhibitor. VOR shows pro-cognitive activity in animal models and beneficial effects on cognitive dysfunction in major depressive patients. Here we compared the effects of 14-day treatments with VOR and escitalopram (ESC, selective serotonin reuptake inhibitor) on neuronal activity in the medial prefrontal cortex (mPFC). Ten groups of rats (5 standard, 5 depleted of 5-HT with p-chlorophenylalanine -pCPA-, used as model of cognitive impairment) were fed with control food or with two doses of VOR-containing food. Four groups were implanted with minipumps delivering vehicle or ESC 10 mg/kg·day s.c. The two VOR doses enable occupation by VOR of SERT+5-HT3-R and all targets, respectively, and correspond to SERT occupancies in patients treated with 5 and 20 VOR mg/day, respectively. Putative pyramidal neurons (n = 985) were recorded extracellularly in the mPFC of anesthetized rats. Sub-chronic VOR administration (but not ESC) significantly increased neuronal discharge in standard and 5-HT-depleted conditions, with a greater effect of the low VOR dose in standard rats. VOR increased neuronal discharge in infralimbic (IL) and prelimbic (PrL) cortices. Hence, oral VOR doses evoking SERT occupancies similar to those in treated patients increase mPFC neuronal discharge. The effect in 5-HT-depleted rats cannot be explained by an antagonist action of VOR at 5-HT3-R and suggests a non-canonical interaction of VOR with 5-HT3-R. These effects may underlie the superior pro-cognitive efficacy of VOR compared with SSRIs in animal models.
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.
Maurizio S
MS
Riga
Department of Human Anatomy and Embriology, Faculty of Medicine and Odontology, University of Valencia, Spain.
Vicent
V
Teruel-Martí
Lundbeck A/S Valby, Denmark.
Connie
C
Sánchez
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.
Pau
P
Celada
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain. Electronic address: francesc.artigas@iibb.csic.es.
Francesc
F
Artigas
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D015283:Citalopram / Q000008:administration & dosage*; D008297:Male; D010879:Piperazines / Q000008:administration & dosage*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D013440:Sulfides / Q000008:administration & dosage*; D000078784:Vortioxetine
D000928:Antidepressive Agents; D015283:Citalopram; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; D000078784:Vortioxetine
5-HT(3) receptors; 5-hydroxytryptamine (serotonin); Antidepressants; Medial prefrontal cortex; Pyramidal neurons