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      Effects of acute and sustained administration of vortioxetine on the serotonin system in the hippocampus: electrophysiological studies in the rat brain

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          Abstract

          Rationale

          Vortioxetine is a novel multimodal antidepressant that is a 5-HT 1B receptor partial agonist, a 5-HT 1A receptor agonist, an inhibitor of the serotonin (5-HT) transporter, and a 5-HT 1D, 5-HT 3, and 5-HT 7 receptor antagonist in vitro. In vivo studies have shown that vortioxetine enhances levels of 5-HT and desensitizes 5-HT 1A autoreceptors.

          Objectives

          The aim of the present study was to investigate the effects of acute and long-term administration of vortioxetine on the terminal 5-HT 1B receptor and the tonic activation of 5-HT 1A receptor in the rat hippocampus.

          Methods

          These receptors were assessed following vortioxetine administration acutely or subcutaneously using minipumps for 14 days. These studies were carried out using in vivo electrophysiological recording, microiontophoresis, and stimulation of the ascending 5-HT fibers.

          Results

          Vortioxetine enhanced the inhibitory effect of the stimulation of the 5-HT bundle at a high, but not low frequency and reversed the inhibitory effect of the 5-HT 1B receptor agonist CP 94253. These results indicate that this compound acted as a 5-HT 1B receptor partial agonist. Vortioxetine inhibited 5-HT reuptake but did not dampen the sensitivity of postsynaptic 5-HT 1A receptors on pyramidal neurons. Long-term administration of vortioxetine and escitalopram (both at 5 mg/kg/day) induced an increase of tonic activation of the 5-HT 1A receptors in CA3 pyramidal neurons, resulting in an increase in 5-HT transmission. In addition, vortioxetine decreased the function of terminal 5-HT 1B autoreceptor following its sustained administration.

          Conclusions

          Desensitization of 5-HT 1B autoreceptor and an increase of tonic activation of 5-HT 1A receptors in the hippocampus may contribute to the antidepressant effect of vortioxetine.

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          Most cited references33

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          Current advances and trends in the treatment of depression.

          P. Blier, C Bancon-Montigny (1994)
          The pathophysiology of major affective illness is poorly understood. However, several lines of preclinical and clinical evidence indicate that an enhancement of 5-HT-mediated neurotransmission might underlie the therapeutic effect of most antidepressant treatments. This net effect would, however, be obtained via different mechanisms. A better understanding of the neurobiological basis for the delayed onset of action of antidepressant treatments has led to the elaboration of strategies that could accelerate the antidepressant response. These strategies are discussed in this article by Pierre Blier and Claude de Montigny.
          Article 0 comments Cited 105 times – based on 0 reviews     Review now
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            Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder.

            J. G. Smith, Justin S. Hogg, A Mørk … (2011)
            The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic β(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.
            Article 0 comments Cited 97 times – based on 0 reviews     Review now
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              Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study.

              Doug Hussey, Sylvain Houle, A V Carella … (2004)
              Minimum therapeutic doses of paroxetine and citalopram produce 80% occupancy for the serotonin (5-HT) transporter (5-HTT). The authors used [(11)C]DASB positron emission tomography to measure occupancies of three other selective serotonin reuptake inhibitors (SSRIs) at minimum therapeutic doses. The relationship between dose and occupancy was also investigated. Striatal 5-HTT binding potential was measured in 77 subjects before and after 4 weeks of medication administration. Binding potential is proportional to the density of receptors not blocked by medication. Subjects received citalopram, fluoxetine, sertraline, paroxetine, or extended-release venlafaxine. Healthy subjects received subtherapeutic doses; subjects with mood and anxiety disorders received therapeutic doses. Percent reduction in 5-HTT binding potential for each medication and dose was calculated. To obtain test-retest data, binding potential was measured before and after 4 weeks in six additional healthy subjects. Substantial occupancy occurred at subtherapeutic doses for all SSRIs. Compared to test-retest data, each drug at the minimum therapeutic dose had a significant effect on striatal 5-HTT binding potential. Mean occupancy at this dose was 76%-85%. At higher plasma SSRI concentrations, 5-HTT occupancy tended to increase above 80%. For each drug, as the dose (or plasma level) increased, occupancy increased nonlinearly, with a plateau for higher doses. At tolerable doses, SSRIs have increasing occupancy with increasing plasma concentration or dose. Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses. This suggests that 80% 5-HTT blockade is important for therapeutic effect. Occupancy should be measured during development of antidepressant compounds targeting the 5-HTT.
              Article 0 comments Cited 80 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Mostafa El Mansari: (613)-722-6521 , mostafa.elmansari@theroyal.ca
                Journal
                Journal ID (nlm-ta): Psychopharmacology (Berl)
                Journal ID (iso-abbrev): Psychopharmacology (Berl.)
                Title: Psychopharmacology
                Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )
                ISSN (Print): 0033-3158
                ISSN (Electronic): 1432-2072
                Publication date (Electronic): 11 February 2015
                Publication date PMC-release: 11 February 2015
                Publication date (Print): 2015
                Volume: 232
                Issue: 13
                Pages: 2343-2352
                Affiliations
                University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, ON K1Z 7K4 Canada
                Article
                Publisher ID: 3870
                DOI: 10.1007/s00213-015-3870-9
                PMC ID: 4464372
                PubMed ID: 25665528
                SO-VID: 27852bb5-cb44-4d78-bdea-1cba5667bea8
                Copyright © © The Author(s) 2015
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Date received : 7 August 2014
                Date accepted : 14 January 2015
                Categories
                Subject: Original Investigation
                Custom metadata
                issue-copyright-statement © Springer-Verlag Berlin Heidelberg 2015

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: electrophysiology,serotonin,hippocampus,vortioxetine,escitalopram,5-ht1a receptor,5-ht1b receptor
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: electrophysiology, serotonin, hippocampus, vortioxetine, escitalopram, 5-ht1a receptor, 5-ht1b receptor

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