Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence

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Abstract

Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such as anxiety and depression. It is well described in the current literature that the brain expresses seven types of 5-HT receptors comprising eighteen distinct subtypes. In this article, we comprehensively reviewed 5-HT1-7 receptors. Of the eighteen 5-HT receptors known today, thirteen are G protein-coupled receptors (GPCRs) and represent targets for approximately 40% of drugs used in humans. Signaling pathways related to these receptors play a crucial role in neurodevelopment and can be modulated to develop effective therapies to treat anxiety and depression. This review presents the experimental evidence of the modulation of the “serotonergic receptosome” in the treatment of anxiety and depression, as well as demonstrating state-of-the-art research related to phytochemicals and these disorders. In addition, detailed aspects of the pharmacological mechanism of action of all currently known 5-HT receptor families were reviewed. From this review, it will be possible to direct the rational design of drugs towards new therapies that involve signaling via 5-HT receptors.

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Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments

Ronald S. Duman, Gerard Sanacora, John Krystal (2019)

The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent models are beginning to yield promising insights. These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients. Studies of the neurobiological basis of the these alterations have focused on both the principle, excitatory glutamate neurons, as well as inhibitory GABA interneurons. They demonstrate structural, functional, and neurochemical deficits in both major neuronal types that could lead to degradation of signal integrity in cortical and hippocampal regions. The molecular mechanisms underlying these changes have not been identified but are thought to be related to stress induced excitotoxic effects in combination with elevated adrenal glucocorticoids and inflammatory cytokines, (as well as other environmental factors). Transcriptomic studies are beginning to demonstrate important sex differences and together with genomic studies are starting to reveal mechanistic domains of overlap and uniqueness with regards to risk and pathophysiological mechanisms with schizophrenia and bipolar disorder. These studies also implicate GABA and glutamate dysfunction as well as immunologic mechanisms. While current antidepressants have significant time lag and efficacy limitations, new, rapid acting agents that target the glutamate and GABA systems address these issues and offer superior therapeutic interventions for this widespread and debilitating disorder. The review by Duman and colleagues discusses evidence that depression is characterized by deficits of excitatory and inhibitory neurons, while new rapid acting agents that target the glutamate and GABA systems address these issues and offer superior therapeutic interventions.

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Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action.

Guillaume Lucas, C Bisgaard, Vladimir Rymar … (2007)

Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.

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Serotonin 5-HT(2C) receptors regulate anxiety-like behavior.

Laurence Tecott, L. Zhou, Lora Heisler … (2007)

Central serotonin (5-hydroxytryptamine, 5-HT) systems have been implicated in the pathophysiology and treatment of anxiety disorders, which are among the world's most prevalent psychiatric conditions. Here, we report that the 5-HT(2C) receptor (5-HT(2C)R) subtype is critically involved in regulating behaviors characteristic of anxiety using male 5-HT(2C)R knockout (KO) mice. Specific neural substrates underlying the 5-HT(2C)R KO anxiolytic phenotype were investigated, and we report that 5-HT(2C)R KO mice display a selective blunting of extended amygdala corticotropin-releasing hormone neuronal activation in response to anxiety stimuli. These findings illustrate a mechanism through which 5-HT(2C)Rs affect anxiety-related behavior and provide insight into the neural circuitry mediating the complex psychological process of anxiety.

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Author and article information

Contributors

Woo-Yang Kim: Role: Academic Editor

Caroline Sevoz-Couche: Role: Academic Editor

Journal

Journal ID (nlm-ta): Pharmaceuticals (Basel)

Journal ID (iso-abbrev): Pharmaceuticals (Basel)

Journal ID (publisher-id): pharmaceuticals

Title: Pharmaceuticals

Publisher: MDPI

ISSN (Electronic): 1424-8247

Publication date (Electronic): 12 February 2021

Publication date Collection: February 2021

Volume: 14

Issue: 2

Electronic Location Identifier: 148

Affiliations

[1 ]Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; stefania.lavorato@ 123456ufob.edu.br (S.N.L.); marinameirelles@ 123456ymail.com (M.M.P.); pablinny.galdino@ 123456ufob.edu.br (P.M.G.d.C.); vanessa.rescia@ 123456ufob.edu.br (V.C.R.); milacunha035@ 123456gmail.com (M.S.C.); manoel.magalhaes17@ 123456gmail.com (M.F.d.M.-F.); luis.p7776@ 123456ufob.edu.br (L.F.P.); adryano.carvalho@ 123456ufob.edu.br (A.A.V.d.C.)

[2 ]Department of Pharmacology, Center for Biological Sciences, Federal University of Paraná, Jardim das Américas, Caixa. postal 19031, Curitiba CEP 81531-990, PR, Brazil; boerngen@ 123456hotmail.com

[3 ]Collegiate Biomedicine, SulAmérica College, Rua Gláuber Rocha, 66, Jardim Paraíso, Luís Eduardo Magalhães CEP 47850-000, BA, Brazil; laisleite@ 123456sulamericafaculdade.edu.br

[4 ]Laboratory of Pharmacology of Toxins (LabTox), Graduate Program in Pharmacology and Medicinal Chemistry (PPGFQM), Institute of Biomedical Sciences (ICB) Federal Universityof Rio de Janeiro (UFRJ), Avenida Carlos Chagas Filho, 373, Cidade Universitária, Rio de Janeiro CEP 21941-590, RJ, Brazil; matheus-sth@ 123456hotmail.com

[5 ]Teaching and Research Manager at the University Hospital—Federal University of Grande Dourados (HU/EBSERH-UFGD), Federal University of Grande Dourados, Rua Ivo Alves da Rocha, 558, Altos do Indaiá, Dourados CEP 79823-501, MS, Brazil; luiz.lopes@ 123456ebserh.gov.br

[6 ]Nucleus of Studies on Infectious Agents and Vectors (Naive), Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; luiz.oliveira@ 123456ufob.edu.br

[7 ]Pharmaceutical Sciences, Food and Nutrition College, Federal University of Mato Grosso do Sul, Avenida Costa e Silva, s/n°, Bairro Universitário, Campo Grande CEP 79070-900, MS, Brazil; saulo.e@ 123456ufms.br

[8 ]Faculty of Biological and Health Sciences, Unigran Capital University Center, RuaBalbina de Matos, 2121, Jarddim Universitário, Dourados CEP 79.824-900, MS, Brazil; anapaulastefanello@ 123456hotmail.com

[9 ]Department of Pharmacology and Therapeutics, State University of Maringá, Avenida Colombo, n° 5790, Jardim Universitário, Maringá CEP 87020-900, PR, Brazil; rkncuman@ 123456uem.br (R.K.N.C.); franciellimss@ 123456gmail.com (F.M.d.S.S.-C.)

[10 ]Department of Biochemistry, State Universityof Maringá, Avenida Colombo, n° 5790, Jardim Universitário, Maringá CEP 87020-900, PR, Brazil; jfcomar@ 123456uem.br

[11 ]Nacional Cancer Institute (INCA), Rua Visconde de Santa Isabel, 274, Rio de Janeiro CEP 20560-121, RJ, Brazil; luana.brasileiro@ 123456inca.gov.br

[12 ]Natu Flora, Rua José Rocha, n° 239, Barreiras CEP 47.800-184, BA, Brazil; leide-neves@ 123456hotmail.com

[13 ]Research Group on Biodiversity and Health (BIOSA), Center for Training in Health Sciences, Federal University of Southern Bahia, Praça Joana Angélica, 58, São José, Teixeira de Freitas CEP 45988-058, BA, Brazil; william.freitas@ 123456ufsb.edu.br

[14 ]Pharmacy Department, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; kleao@ 123456ufob.edu.br (K.V.L.); gomes.jonatas@ 123456gmail.com (J.G.d.S.); raphael.klein@ 123456ufob.edu.br (R.C.K.); mary.klein@ 123456ufob.edu.br (M.H.F.K.)

[15 ]Institute of the Spine and Pain Clinic, Rua Dr. Renato Gonçalves, 108, Renato Gonçalves, Barreiras CEP 47806-021, BA, Brazil; Drbrunoramos@ 123456hotmail.com

[16 ]University Center of Montes Belos, Av. Hermógenes Coelho s/n, Setor Universitário, São Luís de Montes Belos CEP 76100-000, GO, Brazil; cristianekarla01@ 123456hotmail.com

[17 ]Gaus College and Course, Rua Severino Vieira, 60, Centro, Barreiras CEP 47800-160, BA, Brazil; dayane-gaby@ 123456hotmail.com

[18 ]Faculty of Health Sciences, Federal University of Grande Dourados, Dourados Rodovia Dourados, Itahum Km 12, Cidade Universitaria, Caixa postal 364, Dourados CEP 79804-970, MS, Brazil; silviaoesterreich@ 123456gmail.com

Author notes

[* ]Correspondence: gustavo.villasboas@ 123456gmail.com ; Tel.: +55-(77)-3614-3152

Author information

Gustavo R. Villas-Boas https://orcid.org/0000-0003-1660-6480

Stefânia N. Lavorato https://orcid.org/0000-0002-8887-8859

Marina M. Paes https://orcid.org/0000-0002-6689-9819

Pablinny M. G. de Carvalho https://orcid.org/0000-0003-2836-5565

Mila S. Cunha https://orcid.org/0000-0003-4291-5180

Jurandir F. Comar https://orcid.org/0000-0002-9518-7589

Luana do A. Brasileiro https://orcid.org/0000-0001-7683-5512

Article

Publisher ID: pharmaceuticals-14-00148

DOI: 10.3390/ph14020148

PMC ID: 7918669

PubMed ID: 33673205

SO-VID: 5fe6bf6d-872b-49f8-9cad-7fc2d86fbecd

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence

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Most cited references 210

Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments

Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action.

Serotonin 5-HT(2C) receptors regulate anxiety-like behavior.

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