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Endocannabinoid System Components As Potential Biomarkers in Psychiatry

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Endocannabinoid System Components As Potential Biomarkers in Psychiatry REVIEW published: 27 April 2020 doi: 10.3389/fpsyt.2020.00315 Endocannabinoid System Components as Potential Biomarkers in Psychiatry Francisco Navarrete 1,2, Mar´ıa Salud Garc´ıa-Gutie´ rrez 1,2, Rosa Jurado-Barba 3,4,5, Gabriel Rubio 2,3,4,6, Ani Gasparyan 1,2, Amaya Austrich-Olivares 1 and Jorge Manzanares 1,2* 1 Instituto de Neurociencias, Universidad Miguel Herna´ ndez-CSIC, Alicante, Spain, 2 Red Tema´ tica de Investigacio´ n Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Edited by: Spain, 3 Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain, 4 Servicio de Psiquiatría, Helge Frieling, Hospital Universitario 12 de Octubre, Madrid, Spain, 5 Departamento de Psicolog´ıa, Facultad de Educacio´ n y Salud, Hannover Medical School, Germany Universidad Camilo Jose´ Cela, Madrid, Spain, 6 Department of Psychiatry, Complutense University of Madrid, Madrid, Spain Reviewed by: Kirsten R. Müller-Vahl, Hannover Medical School, The high heterogeneity of psychiatric disorders leads to a lack of diagnostic precision. Germany Therefore, the search of biomarkers is a fundamental aspect in psychiatry to reach a more Opal Ousley, personalized medicine. The endocannabinoid system (ECS) has gained increasing interest Emory University, United States Amanda Arnold, due to its involvement in many different functional processes in the brain, including the Georgia State University, regulation of emotions, motivation, and cognition. This article reviews the role of the main United States, in collaboration with reviewer OO components of the ECS as biomarkers in certain psychiatric disorders. Studies carried out *Correspondence: in rodents evaluating the effects of pharmacological and geneticmanipulationof Jorge Manzanares cannabinoid receptors or endocannabinoids (eCBs) degrading enzymes were included. [email protected] Likewise, the ECS-related alterations occurring at the molecular level in animal models Specialty section: reproducing some behavioral and/or neuropathological aspects of psychiatric disorders This article was submitted to were reviewed. Furthermore, clinical studies evaluating gene or protein alterations in post- Molecular Psychiatry, mortem brain tissue or in vivo blood, plasma, and cerebrospinal fluid (CSF) samples were a section of the journal Frontiers in Psychiatry analyzed. Also, the results from neuroimaging studies using positron emission Received: 15 January 2020 tomography (PET) or functional magnetic resonance (fMRI) were included. This review Accepted: 30 March 2020 shows the close involvement of cannabinoid receptor 1 (CB1r) in stress regulation and the Published: 27 April 2020 development of mood disorders [anxiety, depression, bipolar disorder (BD)], in post- Citation: traumatic stress disorder (PTSD), as well as in the etiopathogenesis of schizophrenia, Navarrete F, Garc´ıa-Gutie´ rrez MS, Jurado-Barba R, Rubio G, attention deficit hyperactivity disorder (ADHD), or eating disorders (i.e. anorexia and Gasparyan A, Austrich-Olivares A bulimia nervosa). On the other hand, recent results reveal the potential therapeutic action and Manzanares J (2020) Endocannabinoid System of the endocannabinoid tone manipulation by inhibition of eCBs degrading enzymes, as Components as Potential well as by the modulation of cannabinoid receptor 2 (CB2r) activity on anxiolytic, Biomarkers in Psychiatry. antidepressive, or antipsychotic associated effects. Further clinical research studies are Front. Psychiatry 11:315. doi: 10.3389/fpsyt.2020.00315 needed; however, current evidence suggests that the components of the ECS may Frontiers in Psychiatry | www.frontiersin.org 1 April 2020 | Volume 11 | Article 315 Navarrete et al. Endocannabinoid System Biomarkers in Psychiatry become promising biomarkers in psychiatry to improve, at least in part, the diagnosis and pharmacological treatment of psychiatric disorders. Keywords: endocannabinoid system, cannabinoid receptor (CB1r, CB2r), endocannabinoid, biomarker, psychiatry, diagnosis, treatment INTRODUCTION The endocannabinoid system (ECS) components (receptors, ligands, synthesizing and degrading enzymes) have gained a Psychiatric disorders are one of the main causes of disability in special interest because of their critical neuromodulatory the general population (1). According to a recent estimation, involvement in a plethora of functional mechanisms in the psychiatric disorders account for 32.4% of years lived with central nervous system (CNS), including emotional regulation, disability (YLDs) and 13% of disability adjusted life-years motivational behavior, and cognitive function (6, 7). The wide (DALYs), leading the global burden of disease (2). Despite this, distribution of ECS in the brain, together with the effects derived we still have a great lack of knowledge about its neurobiological from its pharmacological modulation on mood or cognition with basis, and clinically applicable biomarkers have been elusive. exogenous cannabinoid compounds, mainly those contained or During the last decades, an increasing effort has been made in the derived from the Cannabis sativa plant, suggests that the search of biomarkers in psychiatry to help in the diagnosis and identification of the functional role of ECS elements in certain prediction of disease progression or treatment response. psychiatric disorders could be a breakthrough to improve However, a clinical biomarker should be validated, sensitive, diagnosis and treatment (8–11). specific, feasible, and easily reproducible, characteristics that Therefore, this review summarizes the findings regarding the make difficult the implementation in this field (3–5). potential involvement of ECS components as biomarkers, mainly in terms of the discovery of new therapeutic approaches, but also from the point of view of its diagnostic, prognostic and predictive Abbreviations: ECS, endocannabinoid system; eCBs, endocannabinois; CB1r, application. For that purpose, studies on animal models and fl cannabinoid receptor 1; CB2r, cannabinoid receptor 2; CSF, cerebrospinal uid; patients have been collected focusing on the most prevalent PET, positron emission tomography; fMRI, functional magnetic resonance; BD, bipolar disorder; PTSD, posttraumatic stress disorder; ADHD, attention deficit psychiatric conditions, including anxiety disorders (3.8%) (12), hyperactivity disorder; YLDs, years lived with disability; DALYs, disability depressive disorders (3.4%) (12), schizophrenia (0.3%) (12), adjusted life-years; CNS, central nervous system; PFC, prefrontal cortex; NAc, bipolar disorder (0.6%) (12), post-traumatic stress disorder nucleus accumbens; Hipp, hippocampus; Amy, amygdala; PVN, paraventricular (7.8%) (13), attention-deficit hyperactivity disorder (2.2%) nucleus; Hyp, hypothalamus; VTA, ventral tegmental area; AEA, anandamide; 2- AG, 2-arachidonoylglycerol; NAPE-PLD, N-acylphosphatidylethanolamine (14), and eating disorders (0.2%) (12). specificphospholipaseD;FAAH,fattyacidamidehydrolase;GPCRs,Gq protein-coupled receptors; DAGL, diacylglycerol; MAGL, monoacylglycerol lipase; ABHD, alpha/beta-hydrolase domain; DSM-5, diagnostic and statistical manual of mental disorders, 5th version; TRPV1, transient receptor potential A BRIEF OVERVIEW OF THE cation channel subfamily V member 1; dlPAG, dorsolateral periaqueductal gray matter; NO, nitric oxide; WT, wild-type; DMH, dorsomedial hypothalamus; BLA, ENDOCANNABINOID SYSTEM basolateral amygdala; EPM, elevated plus maze; LHb, lateral habenula; LC, locus COMPONENTS coeruleus; DRN, dorsal raphe nucleus; NA, noradrenaline; 5-HT, serotonin; HPA axis, hypothalamus–pituitary–adrenal axis; CRH, corticotropin-releasing ECS regulates a number of physiological functions and mediates hormone; CRHR1, corticotropin-releasing hormone type 1 receptor; 5HTT, the crosstalk between different neurotransmitter systems, serotonin transporter; HDAC, histone deacetylase; CUS, chronic unpredictable stress; CB2xP, transgenic mice overexpression CB2r in the brain; BCP, beta- therefore representing a key player in the control of behavioral caryophyllene; THC, tetrahydrocannabinol; MDD, major depressive disorder; responses (15, 16). ECS is a ubiquitous lipid signaling system BDNF, brain-derived neurotrophic factor; TST, tail suspension test; FST, forced distributed throughout the organism that participates in multiple swimming test; CMS, chronic mild stress; FSL, Flinders sensitive line rats; WKY, intracellular signaling pathways (17, 18). Cannabinoid receptors, Wistar Kyoto rats; cKO, conditional knockout; SSRIs, serotonin selective reuptake endogenous ligands or endocannabinoids (eCBs), and their inhibitors; 5HTT, serotonin transporter; rTMS, repeated transcranial magnetic stimulation; ECT, electroconvulsive therapy; ACC, anterior cingulate cortex; PPI, synthesizing and degrading enzymes are the main components prepulse inhibition; NMDAr, N-methyl-D-aspartate receptors; MAM, of the ECS (Figure 1) present in the central and peripheral methylazoxymethanol; SHR, spontaneously hypertensive rat; CNR1P1, nervous system (15, 19) and in many other peripheral tissues cannabinoid receptor interacting protein; Nrg1, neuregulin 1; DLPFC, regulating distinct functions (20). dorsolateral prefrontal cortex; STG, superior temporal gyrus; qRT-PCR, The CB1 receptor (CB1r) is the most abundant G protein- quantitative real time polymerase chain reaction; FEP, first episode psychosis; PBMCs, peripheral blood mononuclear cells; PANSS, positive and negative coupled receptor
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