Trace Amine-Associated Receptors' Role in Immune System Functions.

Trace amines are a separate, independent group of biogenic amines, close in structure to classical monoamine neurotransmitters such as dopamine, serotonin, and norepinephrine that include many products of the endogenous or bacteria-mediated decarboxylation of amino acids. A family of G protein-coupled trace amine-associated receptors (in humans, TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) that senses trace amines was discovered relatively recently. They are mostly investigated for their involvement in the olfaction of volatile amines encoding innate behaviors and their potential contribution to the pathogenesis of neuropsychiatric disorders, but the expression of the TAAR family of receptors is also observed in various populations of cells in the immune system. This review is focused on the basic information of the interaction of trace amines and their receptors with cells of the general immune systems of humans and other mammals. We also overview the available data on TAARs' role in the function of individual populations of myeloid and lymphoid cells. With further research on the regulatory role of the trace amine system in immune functions and on uncovering the contribution of these processes to the pathogenesis of the immune response, a significant advance in the field could be expected. Furthermore, the determination of the molecular mechanisms of TAARs' involvement in immune system regulation and the further investigation of their potential chemotactic role could bring about the development of new approaches for the treatment of disorders related to immune system dysfunctions.

Protein Metabolism Changes and Alterations in Behavior of Trace Amine-Associated Receptor 1 Knockout Mice Fed a High-Fructose Diet.

Trace amines and their receptors are a family of G protein-coupled receptors widely distributed in the central nervous system and periphery. The trace amine-associated receptor 1 (TAAR1) plays a significant role as a therapeutic target for schizophrenia, depression, diabetes, and obesity. In this study, TAAR1 knockout mice and WT groups were tested in conditions of a high-fructose diet. The consumption of a high-fructose diet may be due to the influence on the metabolism processes by dopamine in the brain, neuromotor function, and level of anxiety of TAAR1 knockout mice. During a comparative analysis of behavioral, biochemical, and morphological parameters, significant differences were found between liver and biochemical parameters, the regulation of protein metabolism (AST/ALT ratio, creatine kinase activity, urea), and alterations in behavior. An elevated plus maze analysis showed the influence of fructose and genetic factors on the level of anxiety. A new marker of the grooming microstructure (depression ratio) was tested, which showed high efficiency as a marker of depression-like behavioral changes and a possible association with dopamine-dependent regulation of protein metabolism. These results confirm a possible association of the TAAR1 gene knockout with an increase in catabolic reaction levels by AST/ALT-dependent and possible dopamine-mediated protein metabolism regulation and depression-like behavior.

Comprehensive assessment of the effectiveness of l-carnitine and transresveratrol in rats with diet-induced obesity.

OBJECTIVES: Transresveratrol (Res) and l-carnitine (l-Car) are proposed to alleviate metabolic and immune disorders and increase physical activity in obese individuals. This study aims to estimate the effect of Res and l-Car in rats with diet-induced obesity. METHODS: Male Wistar rats were fed a diet with excess fat and fructose (high-fat high-carbohydrate diet [HFCD]) supplemented with Res and l-Car at doses of 25 and 300 mg/kg of body weight, respectively, for 63 d. An assessment of grip strength, behavioral reactions, as well as biochemical, morphological, and immunological parameters, was performed. RESULTS: Res supplementation did not affect energy consumption, but l-Car increased when animals had free access to feed. Body weight gains were the highest in animals fed the HFCD, lowest in rats receiving the control balanced diet, and intermediate in animals receiving Res and l-Car. Feeding with Res and l-Car canceled the decrease in long-term memory in rats fed the HFCD, as well as reduced anxiety and increased mobility. With both supplements, bilirubin, triglycerides, and low-density lipoprotein levels in the blood plasma returned to normal values, but only l-Car increased the ratio of aspartic and alanine transaminases. In addition, l-Car lowered the levels of leptin and ghrelin and increased transforming growth factor beta 1 in the blood plasma, and consumption of Res was accompanied by a decrease in interleukin-17A and increase in interferon gamma in spleen lysates. Moreover, l-Car reduced the number of cells with lipid inclusions in the liver. CONCLUSIONS: The consumption of Res and l-Car leads to a significant reduction in dyslipidemia and inflammation with potentially favorable changes in behavioral responses.

Effects of Tyrosine and Tryptophan Supplements on the Vital Indicators in Mice Differently Prone to Diet-Induced Obesity.

We studied the effects of the addition of large neutral amino acids, such as tyrosine (Tyr) and tryptophan (Trp), in mice DBA/2J and tetrahybrid mice DBCB receiving a high-fat, high-carbohydrate diet (HFCD) for 65 days. The locomotor activity, anxiety, muscle tone, mass of internal organs, liver morphology, adipokines, cytokines, and biochemical indices of animals were assessed. The Tyr supplementation potentiated increased anxiety in EPM and contributed to a muscle tone increase, a decrease in the AST/ALT ratio, and an increase in protein anabolism in both mice strains. Tyr contributed to a decrease in liver fatty degeneration and ALT reduction only in DBCB that were sensitive to the development of obesity. The addition of Trp caused an increase in muscle tone and potentiated an increase in anxiety with age in animals of both genotypes. Trp had toxic effects on the livers of mice, which was manifested in increased fatty degeneration in DBCB, edema, and the appearance of micronuclei in DBA/2J. The main identified effects of Tyr on mice are considered in the light of its modulating effect on the dopamine neurotransmitter metabolism, while for the Trp supplement, effects were presumably associated with the synthesis of its toxic metabolites by representatives of the intestinal microflora.

Genetic Deletion of Trace-Amine Associated Receptor 9 (TAAR9) in Rats Leads to Decreased Blood Cholesterol Levels.

In the last two decades, interest has grown significantly in the investigation of the role of trace amines and their receptors in mammalian physiology and pathology. Trace amine-associated receptor 9 (TAAR9) is one of the least studied members of this receptor family with unidentified endogenous ligands and an unknown role in the central nervous system and periphery. In this study, we generated two new TAAR9 knockout (TAAR9-KO) rat strains by CRISPR-Cas9 technology as in vivo models to evaluate the role of TAAR9 in mammalian physiology. In these mutant rats, we performed a comparative analysis of a number of hematological and biochemical parameters in the blood. Particularly, we carried out a complete blood count, erythrocyte osmotic fragility test, and screening of a panel of basic biochemical parameters. No significant alterations in any of the hematological and most biochemical parameters were found between mutant and WT rats. However, biochemical studies revealed a significant decrease in total and low-density lipoprotein cholesterol levels in the blood of both strains of TAAR9-KO rats. Such role of TAAR9 in cholesterol regulation not only brings a new understanding of mechanisms and biological pathways of lipid exchange but also provides a new potential drug target for disorders involving cholesterol-related pathology, such as atherosclerosis.

Effects of Tyrosine and Tryptophan in Rats with Diet-Induced Obesity.

Amino acids tyrosine (Tyr) and tryptophan (Trp) play a significant role in the regulation of energy metabolism, locomotor activity, and eating behavior. We studied the possibility of modulating these processes in obesity by increasing the pool of Tyr and Trp in the experimental diet. As a model of obesity, we used Wistar rats fed a diet with an excess specific energy value (HFCD) for 64 days. Trp led to a normalization of the rats' body weight almost to the control level, but increased anxiety-like behavior and decreased long-term memory. The consumption of amino acids resulted in increased grip strength and impairment of short-term memory. The locomotor activity of animals decreased with age as a result of Tyr consumption, while Trp, on the contrary, prevented this. The Tyr supplementation led to the normalization of triglycerides and LDL. In the spleen cell lysates, amino acids suppressed the production of proinflammatory cytokines. The liver tissue morphology showed that the consumption of Tyr noticeably weakened the signs of fatty degeneration. The addition of Trp, on the contrary, led to an unfavorable effect, consisting of the appearance of a high number of large rounded fatty vacuoles. The data obtained indicate a more pronounced anti-inflammatory effect of Tyr as compared to Trp.

Effects of quercetin on the neuromotor function and behavioral responses of Wistar and Zucker rats fed a high-fat and high-carbohydrate diet.

Quercetin can affect some pathological manifestations in obesity. The mechanism underlying the presumed therapeutic effect of quercetin is probably related to the influence on the central processes regulating energy homeostasis. Thus, the purpose of this study was to examine the effect of quercetin on the neuromotor and behavioral functions in Zucker (Z) and Wistar (W) rats with genetically and/or diet-induced obesity. Rats of both strains received balanced or high fat and fructose diet (HFCD) in a 62-day experiment or the same diets supplemented with quercetin at the dose of 50 mg/kg body weight per day. The neuromotor function and behavioral responses were examined using the grip strength test, open field test, elevated plus maze test and conditioned passive avoidance response (CPAR) test. The quercetin potentiated a decrease in anxiety in W rats consumed HFCD and this effect was absent in Z rats with a defect in the leptin receptor gene. In contrast, quercetin increased locomotor activity and impaired short-term memory in the CPAR test only in Z rats with the absence of normal leptin reception. Against the background of the identified changes quercetin exerted significant effects on the lipid and nitrogen metabolism indices such as HDL cholesterol, AsAT/AlAT activities ratio, urea level as well as body and fat mass that were different in Z and W rats. The data obtained show that the effects of quercetin on behavior vary significantly between two strains of rat and consequently are mediated by processes of leptin reception.

Comparative analysis of the influence of a high-fat/high-carbohydrate diet on the level of anxiety and neuromotor and cognitive functions in Wistar and DAT-KO rats.

We compared anxiety, neuromotor, and cognitive functions in mutant rats with different allelic variants of dopamine transporter DAT knockout receiving balanced or excess in fat and fructose diet. The experiments were performed in DAT-/- homozygotes, DAT+/- heterozygotes, and DAT+/+ wild type rats. The genotype of DAT-KO rats was confirmed by restriction analysis of DAT gene compared to behavioral responses in the open field test (OF). Animals in the first groups of each strain were fed a balanced AIN93M diet; and those in the second groups with a high-fat/high-fructose diet. Neuromotor function was studied as grip strength, and behavioral responses were assessed in the elevated plus maze and conditioned passive avoidance response tests. The mass of the internal organs and white and brown fat, as well as selected lipid and nitrogen metabolism parameters in blood plasma were determined at the end of the experiment. DAT-/- had the highest specific grip strength, and showed an increase in initial exploratory activity in comparison with DAT+/- and DAT +/+. The exploratory activity was significantly reduced in the second test compared to the first one in DAT-/- and DAT+/- of first but not second group. Anxiety decreased with age in the second groups of DAT+/- and DAT+/+ (but not in DAT-/-) and was higher in DAT+/+ than in DAT+/- and DAT-/-. Excess fat and fructose resulted in the deterioration of short-term memory in DAT+/+. Lipidomic indices of blood plasma were less responsive to diet in DAT-/- and DAT-/+ in comparison to DAT+/+. The increased AsAT/AlAT activity ratio in DAT-/- compared with those in DAT+/+ suggests the activation of catabolism activity in the mutants. The consumption of excess fat and fructose significantly modified the effects produced by DAT gene allelic variants presumably due to the influence on the processes of dopamine metabolism.

Understanding autism and other neurodevelopmental disorders through experimental translational neurobehavioral models.

Neurodevelopmental disorders (NDDs) are highly prevalent and severely debilitating brain illnesses caused by aberrant brain growth and development. Resulting in cognitive, social, motor, language and affective disabilities, common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Affecting neurogenesis, glia/neuronal proliferation and migration, synapse formation and myelination, aberrant neural development occurs over a substantial period of time. Genetic, epigenetic, and environmental factors play a key role in NDD pathogenesis. Animal models are an indispensable tool to study NDDs. Paralleling clinical findings, we comprehensively evaluate various preclinical tests and models which target key (social, cognitive, motor) neurobehavioral domains of ASD and other common NDDs. Covering both traditional (rodent) and alternative NDD models, we outline the emerging areas of research and emphasize how preclinical models play a key role in gaining translational and mechanistic insights into NDDs and their therapy.

Improving treatment of neurodevelopmental disorders: recommendations based on preclinical studies.

INTRODUCTION: Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task. AREAS COVERED: Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies. EXPERT OPINION: To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or "hidden heritability," and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.