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Olfactory sensory neurons express a large family of odorant receptors (ORs) and a small family of trace amine-associated receptors (TAARs). While both families are subject to so-called singular expression (expression of one allele of one gene), the mechanisms underlying TAAR gene choice remain obscure. Here, we report the identification of two conserved sequence elements in the mouse TAAR cluster (T-elements) that are required for TAAR gene expression. We observed that cell-type-specific expression of a TAAR-derived transgene required either T-element. Moreover, deleting either element reduced or abolished expression of a subset of TAAR genes, while deleting both elements abolished olfactory expression of all TAARs in cis with the mutation. The T-elements exhibit several features of known OR enhancers but also contain highly conserved, unique sequence motifs. Our data demonstrate that TAAR gene expression requires two cooperative cis-acting enhancers and suggest that ORs and TAARs share similar mechanisms of singular expression., How olfactory sensory neurons express one allele of one TAAR gene is not well understood. Here the authors identify two cooperative cis-acting enhancers that govern TAAR gene choice and that share both similarities and differences with known olfactory enhancers.

Trace Amine-Associated Receptors (TAARs) are a family of G protein-coupled receptors that function as odorant receptors in the main olfactory system of vertebrates. TAARs are monoallelically expressed in primary sensory neurons where they couple to the same transduction cascade as canonical olfactory receptors and are mapped onto glomeruli within a specific region of the olfactory bulb. TAARs have a high affinity for volatile amines, a class of chemicals that are generated during the decomposition of proteins and are ubiquitous physiological metabolites that are found in body fluids. Thus, amines are proposed to play an important role in intra- and interspecific communication such as signaling the sex of the conspecific, the quality of the food source, or even the proximity of a predator. TAARs have a crucial role in the perception of these behaviorally relevant compounds as the genetic deletion of all or even individual olfactory TAARs can alter the behavioral response and reduce the sensitivity to amines. The small size of this receptor family combined with the ethological relevance of their ligands, makes the TAARs an attractive model system for probing olfactory perception. This review will summarize the current knowledge on the olfactory TAARs and discuss whether they represent a unique subsystem within the main olfactory system.

Background/aims Trace amines (TA) are small organic compounds that have neuromodulator activity due to their interaction with some neuron-related receptors, such as trace amine associated receptors (TAARs), α2-adrenergic receptor (α2-AR) and s-adrenergic receptor (s-AR). However, there is little information on whether TA and dopamine (DOP) can interact with other adrenergic receptors (ARs) such as the mammalian α1-AR and the bacterial counterpart QseC, which is involved in quorum sensing of some Gram-negative pathogens. The aim of this study was to investigate the interaction of TA and DOP with α1-AR and QseC. Methods We performed an in silico study using 3D structure from SWISS MODEL and analyzed the protein interaction via molecular docking using PyMol, PoseView and PyRX 8.0. For the in vitro study, we investigated the QseC kinase activity by measuring the remaining ATP in a reaction containing QseC-enriched membrane incubated together with purified QseB and EPI, TA, DOP, or PTL respectively. We also measured the intracellular Ca++ levels, which represents the α1-AR activation, in LNCAP (pancreatic cell line) cells treated with EPI, TA, DOP and PTL respectively using a fluorescence-based assay. The LNCAP cell proliferation was measured using an MTT-based assay. Results Our in silico analysis revealed that TAs and DOP have high binding affinity to the human α1-AR and the bacterial adrenergic receptor (QseC), comparable to epinephrine (EPI). Both are membrane-bound kinases. Experimental studies with pancreatic cell line (LNCAP) showed that the TAs and DOP act as α1-AR antagonist by counteracting the effect of EPI. In the presence of EPI, TA and DOP trigger an increase of the intracellular Ca++ levels in the LNCAP cells leading to an inhibition of cell proliferation. Although in silico data suggest an interaction of TA and DOP with QseC, they do not inhibit the kinase activity of QseC, a histidine kinase receptor involved in quorum sensing which is also sensitive to EPI. Conclusion Our study showed that the TAs and DOP act as α1-AR antagonist but no effect was observed for QseC.

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in pre-limbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT1A receptors but no appreciable action at dopamine D2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schizophrenia and effects of ketamine relevant to its therapeutic use for treating major depression.

We reported recently that activators of AMP-activated protein kinase (AMPK) slow the rundown of current evoked by the D2 autoreceptor agonist quinpirole in rat substantia nigra compacta (SNC) dopamine neurons. The present study examined the effect of AMPK on current generated by dopamine, which unlike quinpirole, is a substrate for the dopamine transporter (DAT). Using whole-cell patch-clamp, we constructed current–voltage (I–V) plots while superfusing brain slices with dopamine (100 μM) for 25 min. Two minutes after starting superfusion, dopamine evoked a peak current with an average slope conductance of 0.97 nS and an estimated reversal potential (Erev) of −113 mV, which is near that expected for K+. But after 10 min of superfusion, dopamine-evoked currents had shifted to more depolarized values with a slope conductance of 0.64 nS and an Erev of −83 mV. This inward shift in current was completely blocked by the DAT inhibitor GBR12935. However, an AMPK blocking agent (dorsomorphin) permitted the emergence of inward current despite the continued presence of the DAT inhibitor. When D2 autoreceptors were blocked by sulpiride, I–V plots showed that dopamine evoked an inward current with an estimated slope conductance of 0.45 nS with an Erev of −57 mV. Moreover, this inward current was completely blocked by the trace amine-associated receptor 1 (TAAR1) antagonist EPPTB. These results suggest that dopamine activates a TAAR1-dependent non-selective cation current that is regulated by AMPK.

We provide a comprehensive review of the available evidence on the pathophysiological implications of genetic variants in the human trace amine-associated receptor (TAAR) superfamily. Genes coding for trace amine-associated receptors (taars) represent a multigene family of G-protein-coupled receptors, clustered to a small genomic region of 108 kb located in chromosome 6q23, which has been consistently identified by linkage analyses as a susceptibility locus for schizophrenia and affective disorders. Most TAARs are expressed in brain areas involved in emotions, reward and cognition. TAARs are activated by endogenous trace amines and thyronamines, and evidence for a modulatory action on other monaminergic systems has been reported. Therefore, linkage analyses were followed by fine mapping association studies in schizophrenia and affective disorders. However, none of these reports has received sufficient universal replication, so their status remains uncertain. Single nucleotide polymorphisms intaarshave emerged as susceptibility loci from genome-wide association studies investigating migraine and brain development, but none of the detected variants reached the threshold for genome-wide significance. In the last decade, technological advances enabled single-gene or whole-exome sequencing, thus allowing the detection of rare genetic variants, which may have a greater impact on the risk of complex disorders. Using these approaches, severaltaars(especiallytaar1) variants have been detected in patients with mental and metabolic disorders, and in some cases, defective receptor function has been demonstrated in vitro. Finally, with the use of transcriptomic and peptidomic techniques, dysregulations of TAARs (especially TAAR6) have been identified in brain disorders characterized by cognitive impairment.

Monoamine oxidase B (MAO B) oxidizes trace amine phenylethylamine (PEA), and neurotransmitters serotonin and dopamine in the brain. We reported previously that PEA levels increased significantly in all brain regions, but serotonin and dopamine levels were unchanged in MAO B knockout (KO) mice. PEA and dopamine are both synthesized from phenylalanine by aromatic L-amino acid decarboxylase in dopaminergic neurons in the striatum. A high concentration of PEA in the striatum may cause dopaminergic neuronal death in the absence of MAO B. We isolated the RNA from brain tissue of MAO B KO mice (2-month old) and age-matched wild type (WT) male mice and analyzed the altered genes by Affymetrix microarray. Differentially expressed genes (DEGs) in MAO B KO compared to WT mice were analyzed by Partek Genomics Suite, followed by Ingenuity Pathway Analysis (IPA) to assess their functional relationships. DEGs in MAO B KO mice are involved in brain inflammation and the genesis of GABAnergic neurons. The significant DEGs include four brain injury or inflammation genes (upregulated: Ido1, TSPO, AVP, Tdo2), five gamma-aminobutyric acid (GABA) receptors (down-regulated: GABRA2, GABRA3, GABRB1, GABRB3, GABRG3), five transcription factors related to adult neurogenesis (upregulated: Wnt7b, Hes5; down-regulated: Pax6, Tcf4, Dtna). Altered brain injury and inflammation genes in MAO B knockout mice are involved in various neurological disorders: attention deficit hyperactive disorder, panic disorder, obsessive compulsive disorder, autism, amyotrophic lateral sclerosis, Parkinson’s diseases, Alzheimer’s disease, bipolar affective disorder. Many were commonly involved in these disorders, indicating that there are overlapping molecular pathways.

Beta-phenylethylamine (β-PEA) is a well-known and widespread endogenous neuroactive trace amine found throughout the central nervous system in humans. In this study, we demonstrated the effects of β-PEA on psychomotor, rewarding, and reinforcing behaviors and affective state using the open-field test, conditioned place preference (CPP), self-administration, and ultrasonic vocalizations (USVs) paradigms. We also investigated the role of the dopamine (DA) D1 receptor in the behavioral effects of β-PEA in rodents. Using enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting, we also determined the DA concentration and the DA-related protein levels in the dorsal striatum of mice administered with acute β-PEA. The results showed that acute β-PEA increased stereotypic behaviors such as circling and head-twitching responses in mice. In the CPP experiment, β-PEA increased place preference in mice. In the self-administration test, β-PEA significantly enhanced self-administration during a 2 h session under fixed ratio (FR) schedules (FR1 and FR3) and produced a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement in rats. In addition, acute β-PEA increased 50-kHz USV calls in rats. Furthermore, acute β-PEA administration increased DA concentration and p-DAT and TH expression in the dorsal striatum of mice. Finally, pretreatment with SCH23390, a DA D1 receptor antagonist, attenuated β-PEA-induced circling behavior and β-PEA-taking behavior in rodents. Taken together, these findings suggest that β-PEA has rewarding and reinforcing effects and psychoactive properties, which induce psychomotor behaviors and a positive affective state by activating the DA D1 receptor in the dorsal striatum.

Olfactory sensory neurons (OSNs) are functionally defined by their expression of a unique odorant receptor (OR). Mechanisms underlying singular OR expression are well studied, and involve a massive cross-chromosomal enhancer interaction network. Trace amine-associated receptors (TAARs) form a distinct family of olfactory receptors, and here we find that mechanisms regulating Taar gene choice display many unique features. The epigenetic signature of Taar genes in TAAR OSNs is different from that in OR OSNs. We further identify that two TAAR enhancers conserved across placental mammals are absolutely required for expression of the entire Taar gene repertoire. Deletion of either enhancer dramatically decreases the expression probabilities of different Taar genes, while deletion of both enhancers completely eliminates the TAAR OSN populations. In addition, both of the enhancers are sufficient to drive transgene expression in the partially overlapped TAAR OSNs. We also show that the TAAR enhancers operate in cis to regulate Taar gene expression. Our findings reveal a coordinated control of Taar gene choice in OSNs by two remote enhancers, and provide an excellent model to study molecular mechanisms underlying formation of an olfactory subsystem., In our nose, some neuron subpopulations express a family of trace amine associated receptors (TAARs, smelling e.g., rotten fish). Fei et al. identify two conserved enhancers across placental mammals named TAAR enhancer 1 and 2 that coordinately regulate expression of the entire Taar gene repertoire.

The classic monoamine oxidase inhibitors (MAOIs) tranylcypromine (TCP) and phenelzine (PLZ) are powerful antidepressants that come with an equally powerful stigma, and are thus rarely prescribed-despite their well-established effectiveness. Some of these preconceptions appear to stem from unclarity, as the etiology of a rare but important side effect, 'spontaneous hypertension' (SH)-a significant increase in blood pressure absent dietary tyramine ingestion-remains improperly elucidated. This paper aims at uprooting some of the stigma surrounding MAOIs by advancing the trace amine (TA) theory as the causative underpinning of SH. This theory posits that SH results from the considerable influx of TAs observed following TCP- or PLZ-administration. TAs are known, albeit at greatly supraphysiological levels, to raise blood pressure on account of their propensity to exert potent indirect sympathomimetic effects; additionally, some research posits that TAs may induce vasoconstrictive effects partly or wholly separate therefrom, which would then constitute a second hypertensive mechanism. TAs are endogenous to the human body in low quantities. Both TCP and PLZ cause marked elevations of 2-phenylethylamine (PEA), meta- and para-tyramine (m-/p-TYR), octopamine (OA), and tryptamine (TRYP), following both acute and (sub)chronic administration. This paper holds that TYR plays a pivotal role in causing SH, due to its strong pressor effect. Cautious treatment of SH is advised, given its typically self-limiting nature. The risk of hypotensive overshoots must be taken into account. For severe cases, this paper urges reconsideration, following suitable confirmation trials, of antipsychotics (notably risperidone) as these agents may reduce striatal p-TYR levels.

Early diagnosis of Parkinson’s disease (PD) remains a challenge to date. New evidence highlights the potential clinical value of circulating trace amines (TAs) in early-stage PD and their involvement in disease progression. A new ultra performance chromatography mass spectrometry (UPLC-MS/MS) method was developed to quantify plasmatic TAs, and the catecholamines and indolamines pertaining to the same biochemical pathways. Three groups of subjects were recruited: 21 de novo, drug untreated, PD patients, 27 in treatment PD patients and 10 healthy subjects as controls. Multivariate and univariate data analyses were applied to reveal metabolic changes among the groups in attempt to discover new putative markers for early PD detection and disease progression. Different circulating levels of tyrosine (p = 0.002), tyramine (p 0.75). The findings of this pilot cross-sectional study suggest that biochemical anomalies of the aminergic and indolic neurotransmitters occur in PD patients. Compounds within the TAs family may constitute putative markers for early stage detection and progression of PD.

Octopamine, a trace amine in mammals, is a major neurotransmitter linked to important biological processes in insects. Interestingly, one of the molecular entities responsible for octopamine availability, the octopamine transporter (OAT), has not been identified in certain insect species. For instance, no OAT has been reported in the fly Drosophila melanogaster (Dm), and the molecule involved in octopamine reuptake in Drosophila is not known. Here, we used molecular modeling methodologies to obtain three-dimensional insights for the dopamine transporter (DAT) and OAT in a common agricultural pest insect, Trichoplusia ni (Tni). Our results show several similarities but also significant differences in the general structures of the proteins of Dm and Tni. One important difference is observed in the ligand binding cavity, where a negatively charged amino acid present in both dopamine transporters is replaced by a polar neutral residue in the Trichoplusia OAT. This modification could influence both the binding mode and the driving force involved in the transport mechanism of these amines into neurons of these species. We also obtained data that support the idea that octopamine could bind and possibly be transported by DmDAT. The structural characterization of macromolecules from different insect species is fundamental in the agricultural field to gain insights into the design of new compounds for controlling pests.

The addiction-related behavioural effects of drugs of abuse are mediated by the mesocorticolimbic monoamine systems. We investigated the effects of 3,4-methylenedioxymethamphetamine (MDMA), mephedrone, β-phenylethylamine (β-PEA) methylphenidate (MPH) on dopamine release from mouse perfused nucleus accumbens and prefrontal cortex slices. The fractional release of [3H]-dopamine was measured at rest and in response to field stimulation. The distributions of [3H]-dopamine and its metabolites were determined using high-pressure liquid chromatography. The effect of drugs on [3H]-dopamine uptake was measured in synaptosomal P2 preparations from the frontal cortex and striatum. Similar to MDMA, mephedrone β-PEA increased the resting release of [3H]-dopamine from the nucleus accumbens and prefrontal cortex in a [Ca2+]o-independent manner, and the stimulation-evoked release was also augmented. In contrast, MPH failed to affect the resting release but potentiated the release in response to axonal activity. Similar to dopamine transporter antagonist GBR 12909, mephedrone, MDMA and MPH biphasically inhibited the [3H]-dopamine uptake. The administration of GBR 12909 and nisoxetine, or lowering the bath temperature prevented MDMA, mephedrone and β-PEA from enhancing the resting, cytoplasmic release of [3H]-dopamine, indicating the role of transporters in the release process. We conclude that amphetamine-like drugs of abuse and the trace amine β-PEA excessively increase the [Ca2+]o-independent, non-vesicular release of dopamine from the cytoplasm into the extrasynaptic space and inhibit the high-affinity transporters, thereby maintaining a high ambient, non-synaptic concentration of dopamine that may tonically control the activity of neurons equipped with dopamine receptors and is likely involved in the reinforcing effects and abusive potential of amphetamines.

SummaryOlfactory sensory neurons (OSNs) are functionally defined by their expression of a unique odorant receptor (OR). Mechanisms underlying singular OR expression are well studied, and involve a massive cross-chromosomal enhancer interaction network. Trace amine-associated receptors (TAARs) form a distinct family of olfactory receptors, and here we find that mechanisms regulatingTaargene choice display many unique features. The epigenetic signature ofTaargenes in TAAR OSNs is different from that in OR OSNs. We further identify that two TAAR enhancers conserved across placental mammals are absolutely required for expression of the entireTaargene repertoire. Deletion of either enhancer dramatically decreases the expression probabilities of differentTaargenes, while deletion of both enhancers completely eliminates the TAAR OSN populations. In addition, both of the enhancers are sufficient to drive transgene expression in the partially overlapped TAAR OSNs. We also show that the TAAR enhancers operate incisto regulateTaargene expression. Our findings reveal a coordinated control ofTaargene choice in OSNs by two remote enhancers, and provide an excellent model to study molecular mechanisms underlying formation of an olfactory subsystem.

Study Objectives Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin (ORX) neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear. The neurobiology underlying sleepiness in other central hypersomnolence disorders, narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH), is currently unknown. Methods Eleven biogenic amines including the monoaminergic neurotransmitters and their metabolites and five trace amines were measured in the cerebrospinal fluid (CSF) of 94 drug-free subjects evaluated at the French National Reference Center for Narcolepsy: 39 NT1(orexin-deficient) patients, 31 patients with objective sleepiness non orexin-deficient (NT2 and IH), and 24 patients without objective sleepiness. Results Three trace amines were undetectable in the sample: tryptamine, octopamine, and 3-iodothyronamine. No significant differences were found among the three groups for quantified monoamines and their metabolites in crude and adjusted models; however, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels tended to increase in NT1 compared to other patients after adjustment. Most of the biomarkers were not associated with ORX-A levels, clinical or neurophysiological parameters, but a few biomarkers (e.g. 3-methoxy-4-hydroxyphenylglycol and norepinephrine) correlated with daytime sleepiness and high rapid eye movement (REM) sleep propensity. Conclusions We found no striking differences among CSF monoamines, their metabolites and trace amine levels, and few associations between them and key clinical or neurophysiological parameters in NT1, NT2/IH, and patients without objective sleepiness. Although mostly negative, these findings are a significant contribution to our understanding of the neurobiology of hypersomnolence in these disorders that remain mysterious and deserve further exploration.

Due to a lack of specific or sensitive biomarkers, drug discovery advances have been limited for individuals suffering from irritable bowel syndrome (IBS). While current therapies provide symptomatic relief, inflammation itself is relatively neglected, despite the presence of chronic immune activation and innate immune system dysfunction. Moreover, considering the microgenderome concept, gender is a significant aetiological risk factor. We believe that we have pinpointed a “missing link” that connects gender, dysbiosis, diet, and inflammation in the context of IBS, which may be manipulated as therapeutic target. The trace aminergic system is conveniently positioned at the interface of the gut microbiome, dietary nutrients and by-products, and mucosal immunity. Almost all leukocyte populations express trace amine associated receptors and significant amounts of trace amines originate from both food and the gut microbiota. Additionally, although IBS-specific data are sparse, existing data supports an interpretation in favour of a gender dependence in trace aminergic signalling. As such, trace aminergic signalling may be altered by fluctuations of especially female reproductive hormones. Utilizing a multidisciplinary approach, this review discusses potential mechanisms of actions, which include hyperreactivity of the immune system and aberrant serotonin signalling, and links outcomes to the symptomology clinically prevalent in IBS. Taken together, it is feasible that the additional level of regulation by the trace aminergic system in IBS has been overlooked, until now. As such, we suggest that components of the trace aminergic system be considered targets for future therapeutic action, with the specific focus of reducing oxidative stress and inflammation.

Trace amines, including β-phenylethylamine, p-octopamine, p-tyramine, and tryptamine, are produced in high levels in invertebrates where they play major roles in homeostasis regulation in a manner similar to that of adrenergic systems in mammals (Rutigliano et al. in Front Pharmacol 8:987, 2017; Gainetdinov et al. in Pharmacol Rev 70(3):549-620, 2018; Nagaya et al. in Neurosci Lett 329(3):324-328, 2002). In mammals, however, their levels are very low, initially prompting these molecules to be termed "trace" or "minor" amines in mammals with only a secondary role in the regulation of more abundant biogenic amines including catecholamines and serotonin (Gainetdinov et al. in Pharmacol Rev 70(3):549-620, 2018). The more recent discovery of trace amine-associated receptors (TAARs) revealed major, previously unsuspected roles of the trace amines and has led to increasing interest within the scientific community. For example, TAARs have been proposed to modulate signaling through dopamine (Schwartz et al. in Expert Opin Ther Targets 22(6):513-526, 2018). Furthermore, these receptors are implicated in both numerous physiological functions including regulation of sleep, olfaction, metabolism, and immunity as well in disease (e.g., substance abuse, neuropsychiatric disorders) (Gainetdinov et al. in Pharmacol Rev 70(3):549-620, 2018; Rutigliano et al. in Front Pharmacol 8:987, 2017). Consequently, trace amine and TAAR research is rapidly growing and is of great translational relevance. In this Special Issue, leaders in trace amine and TAAR research offer both reviews and original research papers that cover a wide range of topics from involvement of TAAR signaling in metabolic regulation and neurophysiology to implications of this signaling in neuropsychiatric diseases including substance abuse and schizophrenia. While a diverse range of topics is covered by these works, the common theme running through all of them is the increasing awareness that trace amine and TAAR signaling represent novel signaling mechanisms in the brain and periphery. These topics are both highly timely and of considerable importance not only for those working in the field but also for the neuroscience community at large.

Tyramine is a biogenic trace amine that is generated via the decarboxylation of the amino acid tyrosine. At pico- to nanomolar concentrations, it can influence a multitude of physiological mechanisms, exhibiting neuromodulatory properties as well as cardiovascular and immunological effects. In humans, the diet is the primary source of physiologically relevant tyramine concentrations, which are influenced by a large number of intrinsic and extrinsic factors. Among these factors are the availability of tyrosine in food, the presence of tyramine-producing bacteria, the environmental pH, and the salt content of food. The process of fermentation provides a particularly good source of tyramine in human nutrition. Here, the potential impact of dietary tyramine on human health was assessed by compiling quantitative data on the tyramine content in a variety of foods and then conducting a brief review of the literature on the physiological, cellular, and systemic effects of tyramine. Together, the data sets presented here may allow both the assessment of tyramine concentrations in food and the extrapolation of these concentrations to gauge the physiological and systemic effects in the context of human nutrition.

Two bidentate dihomooxacalix[4]arene receptors bearing phenylurea moieties substituted with electron-withdrawing groups at the lower rim via a butyl spacer (CF3-Phurea 5b and NO2 Phurea 5c) were obtained in the cone conformation in solution, as shown by NMR. The X-ray crystal structure of 5b is reported. The binding affinity of these receptors towards several relevant anions was investigated by 1H NMR, UV-Vis absorption in different solvents, and fluorescence titrations. Compounds 5b and 5c were also tested as ditopic receptors for organic ion pairs, namely monoamine neurotransmitters and trace amine hydrochlorides by 1H NMR studies. The data showed that both receptors follow the same trend and, in comparison with the unsubstituted phenylurea 5a, they exhibit a significant enhancement on their host-guest properties, owing to the increased acidity of their urea NH protons. NO2-Phurea 5c is the best anion receptor, displaying the strongest complexation for F−, closely followed by the oxoanions BzO−, AcO− and HSO4−. Concerning ion pair recognition, both ditopic receptors presented an outstanding efficiency for the amine hydrochlorides, mainly 5c, with association constants higher than 109 M−2 in the case of phenylethylamine and tyramine.

The 2-step synthesis of [1-14 C]tyramine hydrochloride is described with the product being characterized by TLC, HPLC, and UV spectroscopy. Several methods are provided to purify [1-14 C]tyramine hydrochloride, and its storage and stability are also discussed.

Tyramine is found in foodstuffs, the richest being cheeses, sausages, and wines. Tyramine has been recognized to release catecholamines from nerve endings and to trigger hypertensive reaction. Thereby, tyramine-free diet is recommended for depressed patients treated with irreversible inhibitors of monoamine oxidases (MAO) to limit the risk of hypertension. Tyramine is a substrate of amine oxidases and also an agonist at trace amine-associated receptors. Our aim was to characterize the dose-dependent effects of tyramine on human adipocyte metabolic functions. Lipolytic activity was determined in adipocytes from human subcutaneous abdominal adipose tissue. Glycerol release was increased by a fourfold factor with classical lipolytic agents (1 μM isoprenaline, 1 mM isobutylmethylxanthine) while the amine was ineffective from 0.01 to 100 μM and hardly stimulatory at 1 mM. Tyramine exhibited a partial antilipolytic effect at 100 μM and 1 mM, which was similar to that of insulin but weaker than that obtained with agonists at purinergic A1 receptors, α2-adrenoceptors, or nicotinic acid receptors. Gi-protein blockade by Pertussis toxin abolished all these antilipolytic responses save that of tyramine. Indeed, tyramine antilipolytic effect was impaired by MAO-A inhibition. Tyramine inhibited protein tyrosine phosphatase activities in a manner sensitive to ascorbic acid and amine oxidase inhibitors. Thus, millimolar tyramine restrained lipolysis via the hydrogen peroxide it generates when oxidized by MAO. Since tyramine plasma levels have been reported to reach 0.2 μM after ingestion of 200 mg tyramine in healthy individuals, the direct effects we observed in vitro on adipocytes could be nutritionally relevant only when the MAO-dependent hepato-intestinal detoxifying system is overpassed.

This study tested the effects of β-methylphenylethylamine (β-MPEA) and octopamine on contractile parameters of the gastrointestinal tract in rats. We hypothesized that some of their effects result from interactions with trace amine (TA)-associated receptors or serotoninergic 5-hydroxytryptamine (5-HT) receptors. β-MPEA-induced contractions in rat gastric fundus strips under resting tonus conditions, but induced relaxation in preparations that were previously contracted with carbachol. Octopamine relaxed gastric fundus strips maintained at resting tonus or contracted with carbachol. The contractile effect of β-MPEA was reduced by cyproheptadine and methiothepin, antagonists of excitatory 5-HT receptors. The relaxing effect of β-MPEA on gastric fundus was insensitive to pretreatment with N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide (EPPTB) and tropisetron, antagonists of TA1 and 5-HT4 receptors, respectively. Both EPPTB and tropisetron inhibited the relaxant effects of octopamine on carbachol-contracted preparations. Contrarily, EPPTB did not reduce the relaxant effects of RO5263397 (TA1 agonist) or zacopride (5-HT4 agonist). Octopamine, but not β-MPEA, delayed the gastrointestinal transit of a liquid test meal in awaken rats. In isolated preparations of the small intestine under resting conditions, β-MPEA did not alter the basal tonus, but octopamine relaxed it. Intestinal preparations previously contracted with carbachol relaxed after the addition of octopamine and decreased the magnitude of their spontaneous rhythmic contractions in a tropisetron-dependent manner. Thus, β-MPEA and octopamine exerted pharmacological actions on the rat gastrointestinal tract. The excitatory effects of β-MPEA involved 5-HT receptors. Octopamine inhibited the rat gut contractility through the likely involvement of 5-HT4 and TA receptors. Overall, octopamine effectively inhibited rat gastrointestinal transit.