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Trace Amine-Associated Receptors in Neuropsychiatric Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 26550

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Special Issue Editor

Dr. Grazia Rutigliano

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Guest Editor

Department of Pathology, University of Pisa, Pisa, Italy
Interests: psychosis; bipolar disorder; at-risk mental states; thyroid hormone; thyronamine; trace amine-associated receptors; endocrine disruptors

Special Issue Information

Dear Colleagues,

In the two decades since its discovery, pre-clinical evidence has been accumulating about the role of trace amine-associated receptor 1 (TAAR1) in the central nervous system. TAAR1 is a G protein-coupled receptor, widely expressed across the mammalian brain, mainly in limbic and monoaminergic areas involved in the regulation of emotion, cognition and reward. TAAR1 has a tonic inhibitory control on dopaminergic and serotonergic neurotransmission and influences the composition and function of NMDA glutamatergic receptors. TAAR1 knock out (KO) mice are characterized by impairment in sensorimotor gating functions, perseverative and impulsive behaviors, and worse learning performances, which represent phenotypes relevant to neurodevelopmental disorders and schizophrenia. Furthermore, TAAR1-KO mice present an enhanced sensitivity to the addictive effects of amphetamine, methamphetamine, MDMA, and ethanol. These experimental observations prompted the development of TAAR1 agonists to be exploited for the treatment of neuropsychiatric disorders. This Special Issue is dedicated to the recent evidence about the pathophysiological role of TAAR1 in the central nervous system and the exploitation of this recently discovered signaling system as a target for the treatment of neuropsychiatric disorders, also in the presence of co-morbid addictive disorders and metabolic disturbances.

Dr. Grazia Rutigliano
Guest Editor

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Keywords

TAAR1
schizophrenia
addiction
dopamine
glutamate
neurocognition

Published Papers (7 papers)

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Research

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15 pages, 2561 KiB

Open AccessArticle

Trace Amine Associate Receptor 1 (TAAR1) as a New Target for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease

by Damiana Leo, Giorgia Targa, Stefano Espinoza, Agnès Villers, Raul R. Gainetdinov and Laurence Ris

Int. J. Mol. Sci. 2022, 23(14), 7811; https://doi.org/10.3390/ijms23147811 - 15 Jul 2022

Cited by 7 | Viewed by 2249

Abstract

Worldwide, approximately 27 million people are affected by Alzheimer’s disease (AD). AD pathophysiology is believed to be caused by the deposition of the β-amyloid peptide (Aβ). Aβ can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory and involves postsynaptic glutamate receptor phosphorylation and trafficking. Moreover, Aβ seems to be able to reduce glutamatergic transmission by increasing the endocytosis of NMDA receptors. Trace amines (TAs) are biogenic amines that are structurally similar to monoamine neurotransmitters. TAs bind to G protein-coupled receptors, called TAARs (trace amine-associated receptors); the best-studied member of this family, TAAR1, is distributed in the cortical and limbic structures of the CNS. It has been shown that the activation of TAAR1 can rescue glutamatergic hypofunction and that TAAR1 can modulate glutamate NMDA receptor-related functions in the frontal cortex. Several lines of evidence also suggest the pro-cognitive action of TAAR1 agonists in various behavioural experimental protocols. Thus, we studied, in vitro, the role of the TAAR1 agonist RO5256390 on basal cortical glutamatergic transmission and tested its effect on Aβ-induced dysfunction. Furthermore, we investigated, in vivo, the role of TAAR1 in cognitive dysfunction induced by Aβ infusion in Aβ-treated mice. In vitro data showed that Aβ 1–42 significantly decreased NMDA cell surface expression while the TAAR1 agonist RO5256390 promoted their membrane insertion in cortical cells. In vivo, RO5256390 showed a mild pro-cognitive effect, as demonstrated by the better performance in the Y maze test in mice treated with Aβ. Further studies are needed to better understand the interplay between TAAR1/Aβ and glutamatergic signalling, in order to evaluate the eventual beneficial effect in different experimental paradigms and animal models. Taken together, our data indicate that TAAR1 agonism may provide a novel therapeutic approach in the treatments of disorders involving Aβ-induced cognitive impairments, such as AD. Full article

(This article belongs to the Special Issue Trace Amine-Associated Receptors in Neuropsychiatric Disorders)

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13 pages, 1851 KiB

Open AccessArticle

Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

by Carlotta Bon, Ting-Rong Chern, Elena Cichero, Terrence E. O’Brien, Stefano Gustincich, Raul R. Gainetdinov and Stefano Espinoza

Int. J. Mol. Sci. 2022, 23(6), 3127; https://doi.org/10.3390/ijms23063127 - 14 Mar 2022

Cited by 6 | Viewed by 2708

Abstract

Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet^® model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity. Full article

(This article belongs to the Special Issue Trace Amine-Associated Receptors in Neuropsychiatric Disorders)

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12 pages, 1516 KiB

Open AccessCommunication

TAAR1 Expression in Human Macrophages and Brain Tissue: A Potential Novel Facet of MS Neuroinflammation

by David A. Barnes, Dylan A. Galloway, Marius C. Hoener, Mark D. Berry and Craig S. Moore

Int. J. Mol. Sci. 2021, 22(21), 11576; https://doi.org/10.3390/ijms222111576 - 27 Oct 2021

Cited by 15 | Viewed by 4275

Abstract

TAAR1 is a neuroregulator with emerging evidence suggesting a role in immunomodulation. Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Here, we investigate TAAR1 expression in human primary monocytes, peripherally-derived macrophages, and MS brain tissue. RT-qPCR was used to assess TAAR1 levels in MS monocytes. Using a previously validated anti-human TAAR1 antibody and fluorescence microscopy, TAAR1 protein was visualized in lipopolysaccharide-stimulated or basal human macrophages, as well as macrophage/microglia populations surrounding, bordering, and within a mixed active/inactive MS lesion. In vivo, TAAR1 mRNA expression was significantly lower in MS monocytes compared to age- and sex-matched healthy controls. In vitro, TAAR1 protein showed a predominant nuclear localization in quiescent/control macrophages with a shift to a diffuse intracellular distribution following lipopolysaccharide-induced activation. In brain tissue, TAAR1 protein was predominantly expressed in macrophages/microglia within the border region of mixed active/inactive MS lesions. Considering that TAAR1-mediated anti-inflammatory effects have been previously reported, decreased mRNA in MS patients suggests possible pathophysiologic relevance. A shift in TAAR1 localization following pro-inflammatory activation suggests its function is altered in pro-inflammatory states, while TAAR1-expressing macrophages/microglia bordering an MS lesion supports TAAR1 as a novel pharmacological target in cells directly implicated in MS neuroinflammation. Full article

(This article belongs to the Special Issue Trace Amine-Associated Receptors in Neuropsychiatric Disorders)

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22 pages, 7735 KiB

Open AccessArticle

Trace Amine-Associated Receptor 1 Contributes to Diverse Functional Actions of O-Phenyl-Iodotyramine in Mice but Not to the Effects of Monoamine-Based Antidepressants

by Ioannis Mantas, Mark J. Millan, Benjamin Di Cara, Lucianne Groenink, Sylvie Veiga, Laetitia Cistarelli, Mauricette Brocco, Marc Bertrand, Per Svenningsson and Xiaoqun Zhang

Int. J. Mol. Sci. 2021, 22(16), 8907; https://doi.org/10.3390/ijms22168907 - 18 Aug 2021

Cited by 7 | Viewed by 2567

Abstract

Trace Amine-Associated Receptor 1 (TAAR1) is a potential target for the treatment of depression and other CNS disorders. However, the precise functional roles of TAAR1 to the actions of clinically used antidepressants remains unclear. Herein, we addressed these issues employing the TAAR1 agonist, o-phenyl-iodotyramine (o-PIT), together with TAAR1-knockout (KO) mice. Irrespective of genotype, systemic administration of o-PIT led to a similar increase in mouse brain concentrations. Consistent with the observation of a high density of TAAR1 in the medial preoptic area, o-PIT-induced hypothermia was significantly reduced in TAAR1-KO mice. Furthermore, the inhibition of a prepulse inhibition response by o-PIT, as well as its induction of striatal tyrosine hydroxylase phosphorylation and elevation of extracellular DA in prefrontal cortex, were all reduced in TAAR1-KO compared to wildtype mice. O-PIT was active in both forced-swim and marble-burying tests, and its effects were significantly blunted in TAAR1-KO mice. Conversely, the actions on behaviour and prefrontal cortex dialysis of a broad suite of clinically used antidepressants were unaffected in TAAR1-KO mice. In conclusion, o-PIT is a useful tool for exploring the hypothermic and other functional antidepressant roles of TAAR1. By contrast, clinically used antidepressants do not require TAAR1 for expression of their antidepressant properties. Full article

(This article belongs to the Special Issue Trace Amine-Associated Receptors in Neuropsychiatric Disorders)

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20 pages, 1835 KiB

Open AccessArticle

Pattern of TAAR5 Expression in the Human Brain Based on Transcriptome Datasets Analysis

by Anastasia N. Vaganova, Ramilya Z. Murtazina, Taisiia S. Shemyakova, Andrey D. Prjibelski, Nataliia V. Katolikova and Raul R. Gainetdinov

Int. J. Mol. Sci. 2021, 22(16), 8802; https://doi.org/10.3390/ijms22168802 - 16 Aug 2021

Cited by 10 | Viewed by 2573

Abstract

Trace amine-associated receptors (TAAR) recognize organic compounds, including primary, secondary, and tertiary amines. The TAAR5 receptor is known to be involved in the olfactory sensing of innate socially relevant odors encoded by volatile amines. However, emerging data point to the involvement of TAAR5 in brain functions, particularly in the emotional behaviors mediated by the limbic system which suggests its potential contribution to the pathogenesis of neuropsychiatric diseases. TAAR5 expression was explored in datasets available in the Gene Expression Omnibus, Allen Brain Atlas, and Human Protein Atlas databases. Transcriptomic data demonstrate ubiquitous low TAAR5 expression in the cortical and limbic brain areas, the amygdala and the hippocampus, the nucleus accumbens, the thalamus, the hypothalamus, the basal ganglia, the cerebellum, the substantia nigra, and the white matter. Altered TAAR5 expression is identified in Down syndrome, major depressive disorder, or HIV-associated encephalitis. Taken together, these data indicate that TAAR5 in humans is expressed not only in the olfactory system but also in certain brain structures, including the limbic regions receiving olfactory input and involved in critical brain functions. Thus, TAAR5 can potentially be involved in the pathogenesis of brain disorders and represents a valuable novel target for neuropsychopharmacology. Full article

(This article belongs to the Special Issue Trace Amine-Associated Receptors in Neuropsychiatric Disorders)

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13 pages, 2486 KiB

Open AccessArticle

A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

by Omar Taleb, Mohammed Maammar, Christian Klein, Michel Maitre and Ayikoe Guy Mensah-Nyagan

Int. J. Mol. Sci. 2021, 22(13), 6974; https://doi.org/10.3390/ijms22136974 - 28 Jun 2021

Cited by 16 | Viewed by 2777

Abstract

Xanthurenic acid (XA) is a metabolite of the kynurenine pathway (KP) synthetized in the brain from dietary or microbial tryptophan that crosses the blood-brain barrier through carrier-mediated transport. XA and kynurenic acid (KYNA) are two structurally related compounds of KP occurring at micromolar concentrations in the CNS and suspected to modulate some pathophysiological mechanisms of neuropsychiatric and/or neurodegenerative diseases. Particularly, various data including XA cerebral distribution (from 1 µM in olfactory bulbs and cerebellum to 0.1–0.4 µM in A₉ and A₁₀), its release, and interactions with G protein-dependent XA-receptor, glutamate transporter and metabotropic receptors, strongly support a signaling and/or neuromodulatory role for XA. However, while the parent molecule KYNA is considered as potentially involved in neuropsychiatric disorders because of its inhibitory action on dopamine release in the striatum, the effect of XA on brain dopaminergic activity remains unknown. Here, we demonstrate that acute local/microdialysis-infusions of XA dose-dependently stimulate dopamine release in the rat prefrontal cortex (four-fold increase in the presence of 20 µM XA). This stimulatory effect is blocked by XA-receptor antagonist NCS-486. Interestingly, our results show that the peripheral/intraperitoneal administration of XA, which has been proven to enhance intra-cerebral XA concentrations (about 200% increase after 50 mg/kg XA i.p), also induces a dose-dependent increase of dopamine release in the cortex and striatum. Furthermore, our in vivo electrophysiological studies reveal that the repeated/daily administrations of XA reduce by 43% the number of spontaneously firing dopaminergic neurons in the ventral tegmental area. In the substantia nigra, XA treatment does not change the number of firing neurons. Altogether, our results suggest that XA may contribute together with KYNA to generate a KYNA/XA ratio that may crucially determine the brain normal dopaminergic activity. Imbalance of this ratio may result in dopaminergic dysfunctions related to several brain disorders, including psychotic diseases and drug dependence. Full article

(This article belongs to the Special Issue Trace Amine-Associated Receptors in Neuropsychiatric Disorders)

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Review

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22 pages, 1526 KiB

Open AccessReview

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies

by Nina Dedic, Heather Dworak, Courtney Zeni, Grazia Rutigliano and Oliver D. Howes

Int. J. Mol. Sci. 2021, 22(24), 13185; https://doi.org/10.3390/ijms222413185 - 7 Dec 2021

Cited by 52 | Viewed by 8280

Abstract

Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target for neuropsychiatric disorders due to its ability to modulate monoaminergic and glutamatergic neurotransmission. In particular, agonist compounds have generated interest as potential treatments for schizophrenia and other psychoses due to TAAR1-mediated regulation of dopaminergic tone. Here, we review unmet needs in schizophrenia, the current state of knowledge in TAAR1 circuit biology and neuropharmacology, including preclinical behavioral, imaging, and cellular evidence in glutamatergic, dopaminergic and genetic models linked to the pathophysiology of psychotic, negative and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties, as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront, is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings, this provides a rationale for further investigation and development of this new pharmacological class for the treatment of schizophrenia and other psychiatric disorders. Full article

(This article belongs to the Special Issue Trace Amine-Associated Receptors in Neuropsychiatric Disorders)

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