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Background: Receptors for trace amines – trace amine-associated receptors (TAARs) have been known for approximately 20 years. Most of them for a long time were considered as exclusively olfactory receptors, but recent data indicate that they have also both central and peripheral roles outside of the olfactory system. Speaking of their central functions, TAAR1 and TAAR5, for example, are expressed in brain, and involved in the regulation of emotional behavior via modulation of dopaminergic and serotonergic neurotransmission. TAAR2 remains poorly investigated and even less known about its physiology and function in the central nervous system. Meanwhile TAAR5 shares closest homology with TAAR2 among all the other TAARs and there is evidence for heterodimerization between TAAR2 and TAAR1. Here, we investigated brain neurochemistry, behavior and adult neurogenesis of TAAR2-knockout (TAAR2-KO) mice in comparison with wild type controls. Methods: Experiments were conducted on TAAR2-KO and wild type littermate male mice of C57/Bl6 background. Behavioral testing consisted of several tests: open field, elevated plus maze, light-dark box, 2-bottle sucrose deprivation test, digging, marble burying and Porsolt’s forced swimming test. Measurement of brain tissue levels of monoamines and their metabolites were performed by high performance liquid chromatography with electrochemical detection. Expression pattern of TAAR2 was analyzed by assessing LacZ staining in knockout animals. The use of specific markers doublecortin (DCX) and proliferating cell nuclear antigen (PCNA) allowed to directly analyze the number of proliferating neurons, located in canonical neurogenic areas of the brain such as the subventricular zone and the subgranular zone. Mann-Whitney test was used to evaluate the results of behavioral tests and neurochemical analysis.
P.0855 Alterations in behavior, neurochemistry and adult neurogenesis in
trace amine associated receptor 2 (TAAR2) knockout mice
M. Mor1, E. Efimova1, S. Kuvarzin1, N. Katolikova1, A. Kozlova1,
T. Shemyakova1, V Razenkova2, D. Korzhevskii2, R.R. Gainetdinov1
1 Institute of Translational Biomedicine, Saint Petersburg State University, Saint Petersburg, Russia
2 Institute of Experimental Medicine, Saint Petersburg, Russia
Trace amine associated receptors (TAARs) since their discovery in 2001 were considered as a new
neurotransmitter system. Several TAAR family members, such as TAAR1 and TAAR5 are known to have
a modulatory effect on major monoamine systems, which makes them a new target for
pharmacological treatment of neuropsychological disorders, including schizophrenia, substance
dependence, depression and such. TAAR2 receptor represents another member of the family that
could also have similar effects, given its ability to heterodimerize with TAAR1 and its closest homology
with TAAR5. To determine function of TAAR2 receptors a work on TAAR2-knockout mice (TAAR2-KO)
was done to study their neurochemical, histological and behavioral parameters.
The histochemical study of LacZ expression in TAAR2-KO mice
showed that TAAR2 is expressed in several, including limbic,
areas hippocampus, cerebellum, cortex, habenula, raphe
Behavioral testing consisted of several tests: open field,
elevated plus maze, light-dark box, 2-bottle sucrose
deprivation test, digging, marble burying and and Porsolt’s
forced swimming test. TAAR2-KO mice showed increase in
locomotion (Fig. 1). TAAR2-KO mice had no change in anxiety
level and decreased depression-like behavior through reduced
immobilization time in Porsolt forced swimming test (Fig. 2).
Moreover, TAAR2-knockout animals had more pronounced
temperature change in Stress Induced Hyperthermia test.
The study of monoamine level in the brain tissue using HPLC-
EC showed higher concentration of dopamine in the striatum
(Fig. 3) in TAAR2-KO mice and both noradrenaline and
serotonin levels in the hippocampus were decreased.
The use of specific markers doublecortin (DCX) and
proliferating cell nuclear antigen (PCNA) allowed to directly
analyze the number of proliferating neurons, located in
canonical neurogenic areas of the brain such as the
subventricular zone and the subgranular zone. TAAR2-KO
animals had much higher number of both DCX (Fig. 4) and
PCNA expressing cells in canonical neurogenic areas:
subventricular and the subgranular zones.
Our results suggests that TAAR2 is involved in modulation of monoamine systems of brain, affecting
emotional behavior and regulation of adult neurogenesis. Thereby there is potential links between
TAAR-2-mediated olfactory, emotional behavior and adult neurogenesis, revelation of which can lead us
to better understanding of the course of neurological disorders (foremost neurodegenerative) and their
better treatment.
Fig. 1
Fig. 2
Fig. 3
Fig. 4
This study was supported by the Russian Science Foundation grant 19-75-30008
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Full-text available
Trace amine-associated receptors (TAARs) are a class of G-protein-coupled receptors found in mammals. While TAAR1 is expressed in several brain regions, all the other TAARs have been described mainly in the olfactory epithelium and the glomerular layer of the olfactory bulb and are believed to serve as a new class of olfactory receptors sensing innate odors. However, there is evidence that TAAR5 could play a role also in the central nervous system. In this study, we characterized a mouse line lacking TAAR5 (TAAR5 knockout, TAAR5-KO) expressing beta-galactosidase mapping TAAR5 expression. We found that TAAR5 is expressed not only in the glomerular layer in the olfactory bulb but also in deeper layers projecting to the limbic brain olfactory circuitry with prominent expression in numerous limbic brain regions, such as the anterior olfactory nucleus, the olfactory tubercle, the orbitofrontal cortex (OFC), the amygdala, the hippocampus, the piriform cortex, the entorhinal cortex, the nucleus accumbens, and the thalamic and hypothalamic nuclei. TAAR5-KO mice did not show gross developmental abnormalities but demonstrated less anxiety- and depressive-like behavior in several behavioral tests. TAAR5-KO mice also showed significant decreases in the tissue levels of serotonin and its metabolite in several brain areas and were more sensitive to the hypothermic action of serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propilamino)tetralin (8-OH-DPAT). These observations indicate that TAAR5 is not just innate odor-sensing olfactory receptor but also serves to provide olfactory input into limbic brain areas to regulate emotional behaviors likely via modulation of the serotonin system. Thus, anxiolytic and/or antidepressant action of future TAAR5 antagonists could be predicted. In general, “olfactory” TAAR-mediated brain circuitry may represent a previously unappreciated neurotransmitter system involved in the transmission of innate odors into emotional behavioral responses.
Full-text available
The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5 years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders.