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Abnormal genetic polymorphism of trace amine-associated receptor 1 (TAAR1) rs8192620 site has been confirmed to induce methamphetamine (MA) use and drug craving. However, the genetic susceptibility difference between MA addicts and heroin addicts is unknown. This study evaluated genetic heterogeneity of TAAR1 rs8192620 between MA and heroin addicts and elucidated whether rs8192620 genotypes associated with discrepancy in emotional impulsivity, which would help to instruct individualized treatment in addiction via acting on TAAR1 and evaluate risk of varied drug addiction. Participants consisting of gender-matched 63 MA and 71 heroin abusers were enrolled in the study. Due to mixed drug usage in some MA addicts, MA users were further subdivided into 41 only-MA (only MA taking) and 22 mixed-drug (Magu composed of about 20% MA and 70% caffeine) abusers. Via inter-individual single nucleotide polymorphism (SNP) analysis and two-sample t tests, respectively, the genotypic and Barratt Impulsiveness Scale-11 (BIS-11) scores differences between groups were completed. With following genotypic stratification, the differences in BIS-11 scores between groups were analyzed through two-sample t test. Individual SNP analysis showed significant differences in alleles distribution of rs8192620 between MA and heroin subjects (p = 0.019), even after Bonferroni correction. The TT homozygotes of rs8192620 dominated in MA participants, while C-containing genotypes in heroin (p = 0.026). There was no association of genotypes of TAAR1 rs8192620 with addicts' impulsivity. Our research indicates that the TAAR1 gene polymorphism might mediate the susceptibility discrepancy between MA and heroin abuse. [ABSTRACT FROM AUTHOR]

The role of the TAAR1 receptor, one of the trace amine-associated receptors (TAARs) family, in the formation of the behavioral component of the stress response was studied. The behavior of female TAAR1 knockout (TAAR1 KO) mice and wild-type (WT) mice was investigated in tests of elevated plus maze and elevated zero maze (EPM and EZM) and forced swimming test (FST) under normal conditions and after uncontrolled restraint stress exposure for 30 min. In the EPM test, the initial level of locomotor and exploratory activity, as well as the anxiety, was identical in both groups of mice. In the EZM test, the initial indicators of anxiety in female TAAR1 KO mice compared to female WT mice were higher, and locomotor activity was lower. When testing mice in the EZM 30 minutes after the end of stress exposure, it was found that the anxiety in female WT mice sharply increased, and the indicators of locomotor activity and exploratory behavior significantly decreased. The behavioral indicators in the EZM test in TAAR1 KO mice before and after stress were identical. A pronounced behavioral component of the stress response was observed in both TAAR1 KO and WT mice during testing in EPM. There were no significant differences between TAAR1 KO and WT mice during testing in EPM four hours after stress exposure. In the FST test the latency to the first immobility was initially longer in TAAR1 KO mice compared to the WT mice, but 24 hours after the stress this indicator has significantly decreased. As a result, TAAR1 KO and WT mice no longer differed in all behavioral indicators in the FST. Three weeks after acute restraint stress, both TAAR1 KO and WT groups showed a significant increase in immobility duration and a decrease in latency to the first immobility, however no difference between the both groups of animals were found. Thereby, we found the complete absence of behavioral change immediately after stressor exposure in TAAR1 KO compared to the WT mice. [ABSTRACT FROM AUTHOR]

Methamphetamine abuse is a global epidemic associated with a wide-ranging array of adverse effects on the cardiovascular system including dilated cardiomyopathy, malignant and benign arrhythmias, coronary vasospasm, and atherosclerotic coronary artery disease. While the acute behavioral manifestations of amphetamine abuse are the most easily clinically identified, cardiovascular toxicity is common in this patient population and should be considered in this setting due to its high morbidity and mortality. The specific mechanisms for amphetamine cardiotoxicity have not been fully established, but new research implicates activation of several cellular targets including Sigma-1 receptors and trace amine-associated receptor 1 (TAAR1) leading to a myriad of negative downstream effects including increased reactive oxygenating species (ROS), mitochondrial dysfunction, and modulations of intracellular calcium. Additional pathologic effects are mediated by increased circulating catecholamines, which when chronically activated have well-established adverse effects on the cardiovascular system. In this article, we present a case report followed by a current review of the epidemiology, pathophysiology, diagnosis, and treatment modalities of amphetamine-induced cardiovascular disease. [ABSTRACT FROM AUTHOR]

Rationale: Trace amine-associated receptor 1 (TAAR1) is the best-studied receptor of trace amines, a group of biogenic amines expressed at a relatively low level in the mammalian brain. Growing evidence suggests that TAAR1 plays a critical role in various neuropsychiatric disorders. Given that selective TAAR1 agonists were shown to produce pro-cognition and antipsychotic-like effects as well as to suppress drug use and relapse, they have been proposed to be novel treatments for mental disorders such as schizophrenia and addiction. However, the aversive effects of selective TAAR1 agonists remain largely unknown. Objectives: Here, we evaluated whether the selective TAAR1 full agonist RO5166017 and partial agonist RO5263397 could induce conditioned taste aversion (CTA). Results: We found that RO5166017 and RO5263397 produced significant aversions to both saccharin and NaCl taste novelty. Furthermore, RO5166017 produced CTA to saccharin in TAAR1 heterozygous knockout (taar1±) and wild-type rats but not in TAAR1 homozygous knockout rats (taar1−/−), suggesting that TAAR1 was sufficient for the taste aversive stimulus property of RO5166017. Conclusions: Taken together, our data indicate that selective TAAR1 agonists could produce strong CTA. Our study urges careful evaluations of the aversive effects of TAAR1 agonists before translating them to clinical use for the treatment of mental disorders. [ABSTRACT FROM AUTHOR]

Trace amines (TA) are a family of endogenous compounds structurally similar to classical biogenic amines that may be involved in the pathogenesis of a number of neuropsychiatric disorders. One of the most studied and perspective member of the TA associated receptors (TAARs) family is the TAAR1. The aim of the present study was to investigate the sensory gating (SG) in freely moving TAAR1 knockout mice in a chronic experiment. The study of SG was conducted in the paired-click paradigm. The SG indices were calculated as an absolute value by subtracting the second stimulus response amplitude from the first stimulus response amplitude (S1–S2) and as a relative value calculated by dividing the S2 amplitude by the response amplitude on S1 (S2/S1). As a result, a significant decrease in the amplitude of the N40 component was found in TAAR1 knockout mice compared to wild-type mice. In addition, the absolute value of sensory gating calculated by the S1–S2 method was also reduced, but the relative value of sensory gating denoted as S1/S2 ratio remained unchanged. Thus, the data obtained indicate the involvement of TAAR1 in the generation of auditory evoked potentials and the potential involvement of the trace amine system in the dosing and filtering of sensory information. [ABSTRACT FROM AUTHOR]

TAAR1 is known as a neuromodulator of monoaminergic systems, providing the negative regulation of dopaminergic and serotonergic neuronal activity. The TAAR1 ability to regulate monoaminergic systems determines its prominent role in psychiatric and neurological disorders. The present study is aimed to provide further evidence for the role of TAAR1 in mismatch negativity (MMN) generation. The electroencephalogram was recorded in freely moving TAAR1 knockout and wild type mice. As the MMN response reflects a combination of stimulus-specific adaptation (SSA) and deviance detection (DD) response, we compare standard and deviant stimuli to the multi-standard control. The difference observed between the high-adapted standard and low-adapted control stimuli together with the similar response to deviant and control stimuli suggest that the MMN-like response in wild type mice most likely reflects the SSA. On the other hand, TAAR1 knockout mice show no difference between standard, deviant, and control stimuli, probably indicating that the SSA to repetitive stimuli is impaired in TAAR-KO mice. [ABSTRACT FROM AUTHOR]

Purpose: Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A agonist activity currently in clinical development for the treatment of schizophrenia. The objectives of the current study were to characterize the in vitro ADME properties, preclinical PK, and to evaluate the DDI potential of ulotaront and its major metabolite SEP-383103. Methods: Solubility, permeability, plasma protein binding, CYP inhibition and induction, transporter inhibition and uptake studies were conducted in vitro. Phenotyping studies were conducted using recombinant human CYPs and FMOs, human liver microsomes and human liver homogenates. Preclinical plasma and brain pharmacokinetics were determined after a single intraperitoneal, intravenous, and oral administration of ulotaront. Results: Ulotaront is a compound of high solubility, high permeability, and low binding to plasma proteins. Ulotaront metabolism is mediated via both NADPH-dependent and NADPH-independent pathways, with CYP2D6 as the major metabolizing enzyme. Ulotaront is an inducer of CYP2B6, and an inhibitor of CYP2D6, OCT1 and OCT2, while SEP-383103 is neither a CYP inducer nor a potent inhibitor of CYPs and human transporters. Ulotaront exhibits rapid absorption, greater than 70% bioavailability, approximately 3.5 L/kg volume of distribution, 1.5-4 h half-life, 12-43 ml/min/kg clearance, and good penetration across the blood–brain barrier in preclinical species. Conclusions: Ulotaront has been designated as a BCS1 compound by US FDA. The ability of ulotaront to penetrate the blood–brain barrier for CNS targeting has been demonstrated in mice and rats. The potential for ulotaront and SEP-383103 to act as perpetrators of CYP and transporter-mediated DDIs is predicted to be remote. [ABSTRACT FROM AUTHOR]

Rationale: Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that has a particular role in regulating dopaminergic, serotonergic, and glutamatergic transmission. TAAR1 agonists have shown pro-cognitive activities. However, it remains largely unknown of the effects of TAAR1 agonists on memory performance. Objectives: Here, by using the mice novel object recognition (NOR) test, we examined the effects of the selective TAAR1 partial agonist RO5263397 on recognition memory. Results: We found that RO5263397 significantly enhanced the retrieval of short-term memory (STM; 20 min after training) both in male and female mice. RO5263397 promoted the retrieval of STM in the wild-type (WT) littermates but not TAAR1-KO mice, indicating that the effects of RO5263397 were dependent on TAAR1. Interestingly, compared to their WT litters, TAAR1-KO mice showed similar levels of STM, suggesting that genetic deletion of taar1 gene did not affect the STM retrieval. Furthermore, RO5263397 also promoted the retrieval of long-term NOR memory (24 h after training). Conclusions: These results indicate that TAAR1 activation promotes NOR memory retrieval. Consistent with previous studies, our finding further suggests that TAAR1 agonists have pro-cognitive properties. [ABSTRACT FROM AUTHOR]

Amphetamines and amphetamine-derivatives elevate neurotransmitter concentrations by competing with endogenous biogenic amines for reuptake. In addition, AMPHs have been shown to activate endocytosis of the dopamine transporter (DAT) which further elevates extracellular dopamine (DA). We previously found that the biochemical cascade leading to this cellular process involves entry of AMPH into the cell through the DAT, stimulation of an intracellular trace amine-associated receptor, TAAR1, and activation of the small GTPase, RhoA. We also showed that the neuronal glutamate transporter, EAAT3, undergoes endocytosis via the same cascade in DA neurons, leading to potentiation of glutamatergic inputs. Since AMPH is a transported inhibitor of both DAT and the norepinephrine transporter (NET), and EAAT3 is also expressed in norepinephrine (NE) neurons, we explored the possibility that this signaling cascade occurs in NE neurons. We found that AMPH can cause endocytosis of NET as well as EAAT3 in NE neurons. NET endocytosis is dependent on TAAR1, RhoA, intracellular calcium and CaMKII activation, similar to DAT. However, EAAT3 endocytosis is similar in all regards except its dependence upon CaMKII activation. RhoA activation is dependent on calcium, but not CaMKII, explaining a divergence in AMPH-mediated endocytosis of DAT and NET from that of EAAT3. These data indicate that AMPHs and other TAAR1 agonists can affect glutamate signaling through internalization of EAAT3 in NE as well as DA neurons. [ABSTRACT FROM AUTHOR]

Trace amine-associated receptor 1 (TAAR1) is a widely recognized new perspective target for the neuropsychiatric pharmacological treatment. Despite a growing number of studies investigating TAAR1 role in the animal models of different pathologies, information of TAAR1 agonists impact on executive cognitive functions is limited. The goal of the present study was to evaluate the activity of highly selective partial TAAR1 agonist RO5263397 on various executive cognitive functions. The results of the present study demonstrated that the pretreatment with RO5263397 was able to increase attention and decrease cognitive flexibility in rats. The analysis of the RO5263397 action on impulsivity demonstrated that the TAAR1 activation failed to affect premature responding but was able to slightly modify impulsive choice. Problem solving was resistant to the pharmacological intervention. [ABSTRACT FROM AUTHOR]

Since the discovery in 2001, the G protein-coupled trace amine-associated receptor 1 (TAAR1) has become an important focus of research targeted on evaluation of its role in the central nervous system (CNS). Meanwhile, impact of TAAR1 in the peripheral organs is less investigated. Expression of TAAR1 was demonstrated in different peripheral tissues: pancreatic β-cells, stomach, intestines, white blood cells (WBC), and thyroid. However, the role of TAAR1 in regulation of hematological parameters has not been investigated yet. In this study, we performed analysis of anxiety-related behaviors, a complete blood count (CBC), erythrocyte fragility, as well as FT3/FT4 thyroid hormones levels in adult and middle-aged TAAR1 knockout mice. Complete blood count analysis was performed on a Siemens Advia 2120i hematology analyzer and included more than 35 measured and calculated parameters. Erythrocyte fragility test evaluated spherocytosis pathologies of red blood cells (RBC). No significant alterations in essentially all these parameters were found in mice without TAAR1. However, comparative aging analysis has revealed a decreased neutrophils level in the middle-aged TAAR1 knockout mouse group. Minimal alterations in these parameters observed in TAAR1 knockout mice suggest that future TAAR1-based therapies should exert little hematological effect and thus will likely have a good safety profile. [ABSTRACT FROM AUTHOR]