A Novel and Functionally Diverse Class of Acetylcholine-Gated Ion Channels.

Fast cholinergic neurotransmission is mediated by acetylcholine-gated ion channels; in particular, excitatory nicotinic acetylcholine receptors play well established roles in virtually all nervous systems. Acetylcholine-gated inhibitory channels have also been identified in some invertebrate phyla, yet their roles in the nervous system are less well understood. We report the existence of multiple new inhibitory ion channels with diverse ligand activation properties in Caenorhabditis elegans We identify three channels, LGC-40, LGC-57, and LGC-58, whose primary ligand is choline rather than acetylcholine, as well as the first evidence of a truly polymodal channel, LGC-39, which is activated by both cholinergic and aminergic ligands. Using our new ligand-receptor pairs we uncover the surprising extent to which single neurons in the hermaphrodite nervous system express both excitatory and inhibitory channels, not only for acetylcholine but also for the other major neurotransmitters. The results presented in this study offer new insight into the potential evolutionary benefit of a vast and diverse repertoire of ligand-gated ion channels to generate complexity in an anatomically compact nervous system.SIGNIFICANCE STATEMENT Here we describe the diversity of cholinergic signaling in the nematode Caenorhabditis elegans We identify and characterize a novel family of ligand-gated ion channels and show that they are preferentially gated by choline rather than acetylcholine and expressed broadly in the nervous system. Interestingly, we also identify one channel gated by chemically diverse ligands including acetylcholine and aminergic ligands. By using our new knowledge of these ligand-gated ion channels, we built a model to predict the synaptic polarity in the C. elegans connectome. This model can be used for generating hypotheses on neural circuit function.

Disposable biosensor based on ionic liquid, carbon nanofiber and poly(glutamic acid) for tyramine determination.

In this study, an electrochemical biosensor based on carbon nanofibers (CNF), ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (IL), poly(glutamic acid) (PGA) and tyrosinase (Tyr) modified screen printed carbon electrode (SPE) was constructed for tyramine determination. Optimum experimental parameters such as CNF and IL amount, polymerization conditions of glutamic acid, enzyme loading, pH of test solution and operating potential were explored. The construction steps of the Tyr/PGA/CNF-IL/SPE were pursued by scanning electron microscopy and cyclic voltammetry. The Tyr/PGA/CNF-IL/SPE biosensor exhibited linear response to tyramine in the range of 2.0 × 10-7 - 4.8 × 10-5 M with a low detection limit of 9.1 × 10-8 M and sensitivity of 302.6 µA mM-1. The other advantages of Tyr/PGA/CNF-IL/SPE include its high reproducibility, good stability and anti-interference ability. The presented biosensor was also applied for tyramine determination in malt drink and pickle juice samples and mean analytical recoveries of spiked tyramine were calculated as 100.6% and 100.4% respectively.

Tyramine-Mediated Hyperactivity Modulates the Dietary Habits in Helicoverpa armigera.

Helicoverpa armigera exhibits extensive variability in feeding habits and food selection. Neuronal regulation of H. armigera feeding behavior is primarily influenced by biogenic amines such as Tyramine (TA) and Octopamine (OA). The molecular responses of H. armigera to dietary challenges in the presence of TA or OA have yet to be studied. This investigation dissects the impact of OA and TA on H. armigera feeding choices and behaviors under non-host nutritional stress. It has been observed that feeding behavior remains unaltered during the exogenous administration of OA and TA through an artificial diet (AD). Ingestion of higher OA or TA concentrations leads to increased mortality. OA and TA treatment in combination with host and non-host diets results in the induction of feeding and higher locomotion toward food, particularly in the case of TA treatment. Increased expression of markers, prominin-like, and tachykinin-related peptide receptor-like transcripts further assessed increased locomotion activity. Insects subjected to a non-host diet with TA treatment exhibited increased feeding and overexpression of the feeding indicator, the Neuropeptide F receptor, and the feeding regulator, Sulfakinin, compared with other conditions. Expression of sensation and biogenic amine synthesis genesis elevated in insects fed a non-host diet in combination with OA or TA. Metabolomics analysis revealed a decreased concentration of the feeding behavior elicitor, dopamine, in insects fed a non-host diet containing TA. This work highlights the complex interplay between biogenic amine functions during dietary stress and suggests the role of tyramine in feeding promotion under stressed conditions.

Dairy and Headaches: What is the Connection?

PURPOSE OF REVIEWS: Headaches represent a prevalent and burdensome health condition, affecting individuals of all ages worldwide. While dietary factors have been implicated in headache pathophysiology, the association between dairy consumption and headaches remains controversial and inadequately understood. This comprehensive review systematically examines the existing literature to elucidate the relationship between dairy intake and headaches, addressing methodological challenges, potential biases, and gaps in the current knowledge. RECENT FINDINGS: A thorough search of electronic databases identified relevant observational studies, clinical trials, and mechanistic investigations exploring the impact of dairy consumption on headache incidence, frequency, severity, and duration. Methodological considerations, including study design, measurement of exposure and outcome variables, confounding factors, and sources of bias, were critically evaluated to assess the strength of evidence and validity of findings. Despite heterogeneity across studies, emerging evidence suggests a complex and multifaceted relationship between dairy intake and headaches, influenced by individual characteristics, dietary patterns, headache subtype, and study context. While some studies report a positive association between dairy consumption and headaches, others indicate no significant effect or potential therapeutic benefits of dairy restriction. Mechanistic insights suggest plausible biological mechanisms, including neuroinflammatory pathways, neurotransmitter modulation, vascular effects, and gut-brain interactions, which may mediate the observed associations. Future research directions encompass longitudinal studies, mechanistic investigations, stratified analyses, randomized controlled trials, and exploration of the gut microbiota to further elucidate the underlying mechanisms and inform evidence-based dietary recommendations for headache management. This integrative review underscores the importance of interdisciplinary collaboration and personalized approaches to address the complex interplay between diet, headaches, and overall health.

Bacteriocins against biogenic amine-accumulating lactic acid bacteria in cheese: Nisin A shows the broadest antimicrobial spectrum and prevents the formation of biofilms.

Cheese is a food in which toxic concentrations of biogenic amines (BA) may be reached, mainly as a consequence of the decarboxylation of determined amino acids by certain lactic acid bacteria (LAB). To maintain the food safety of cheese, environmentally friendly strategies are needed that specifically prevent the growth of BA-producing LAB and the accumulation of BA. The bacteriocins produced by LAB are natural compounds with great potential as food biopreservatives. This work examines the antimicrobial potential of 7 bacteriocin-containing, cell-free supernatants (CFS: coagulin A-CFS, enterocin A-CFS, enterocin P-CFS, lacticin 481-CFS, nisin A-CFS, nisin Z-CFS and plantaricin A-CFS) produced by LAB against 48 strains of the LAB species largely responsible for the accumulation of the most important BA in cheese, that is, histamine, tyramine, and putrescine. Susceptibility to the different CFS was strain-dependent. The histamine-producing species with the broadest sensitivity spectrum were Lentilactobacillus parabuchneri (the species mainly responsible for the accumulation of histamine in cheese) and Pediococcus parvulus. The tyramine-producing species with the broadest sensitivity spectrum was Enterococcus faecium, and Enterococcus faecalis and Enterococcus hirae were among the most sensitive putrescine producers. Nisin A-CFS was active against 31 of the 48 BA-producing strains (the broadest antimicrobial spectrum recorded). Moreover, commercial nisin A prevented biofilm formation by 67% of the BA-producing, biofilm-forming LAB strains. These findings underscore the potential of bacteriocins in the control of BA-producing LAB and support the use of nisin A as a food-grade biopreservative for keeping BA-producing LAB in check and reducing BA accumulation in cheese.

Fabrication of fluorescence probe based on molecularly imprinted polymers on red emissive biomass-derived carbon dots coupled with smartphone readout for tyramine determination in fermented meat products.

A fluorescence probe based on molecularly imprinted polymers on red emissive biomass-derived carbon dots (r-BCDs@MIPs) was developed to detect tyramine in fermented meat products. The red emissive biomass-derived carbon dots (r-BCDs) were synthesized by the one-step solvothermal method using discarded passion fruit shells as raw materials. The fluorescence emission peak of r-BCDs was at 670 nm, and the relative quantum yield (QY) was about 2.44%. Molecularly imprinted sensing materials were prepared with r-BCDs as fluorescent centers for the detection of trace tyramine, which showed a good linear response in the concentration range of tyramine from 1 to 40 µg L-1. The linear correlation coefficient was 0.9837, and the limit of detection was 0.77 µg L-1. The method was successfully applied to the determination of tyramine in fermented meat products, and the recovery was 87.17-106.02%. The reliability of the results was verified through high-performance liquid chromatography (HPLC). Furthermore, we combined the r-BCDs@MIPs with smartphone-assisted signal readout to achieve real-time detection of tyramine in real samples. Considering its simplicity and convenience, the method could be used as a rapid and low-cost promising platform with broad application prospects for on-site detection of trace tyramine with smartphone-assisted signal readout.

Three new phenylpropanoid glucosides and a new tyramine-type alkamide from Piper puberulum.

Three new phenylpropanoid glycosides, piperpubelide (1), 1-propionyl-3-hydroxy-phenyl-4-O-ß-D-glucopyranoside (2), and 1-propionyl-4-hydroxy-phenyl-3-O-ß-D-glucopyranoside (3), a new tyramine-type alkamide, puberulumine L (4), together with thirteen known compounds (5-17) were isolated from Piper puberulum (Benth.) Maxim. Their structures were elucidated by analysis of spectroscopic data involving NMR, IR, UV, and HRESIMS data. Calculated and experimental ECD was used to confirm the configuration of compound 1. Compounds 14, 16, and 17 exhibited relatively positive DPPH radical scavenging activities, with corresponding EC50 of 10.23, 24.12, and 21.83 µM, respectively. In addition, compound 5 inhibited LPS-induced NO production in BV-2 microglia with an IC50 value of 18.05 µM.

Variation of Cyclodextrin (CD) Complexation with Biogenic Amine Tyramine: Pseudopolymorphs of ß-CD Inclusion vs. α-CD Exclusion, Deep Atomistic Insights.

Tyramine (TRM) is a biogenic catecholamine neurotransmitter, which can trigger migraines and hypertension. TRM accumulated in foods is reduced and detected using additive cyclodextrins (CDs) while their association characteristics remain unclear. Here, single-crystal X-ray diffraction and density functional theory (DFT) calculation have been performed, demonstrating the elusive pseudopolymorphs in ß-CD inclusion complexes with TRM base/HCl, ß-CD·0.5TRM·7.6H2O (1) and ß-CD·TRM HCl·4H2O (2) and the rare α-CD·0.5(TRM HCl)·10H2O (3) exclusion complex. Both 1 and 2 share the common inclusion mode with similar TRM structures in the round and elliptical ß-CD cavities, belong to the monoclinic space group P21, and have similar herringbone packing structures. Furthermore, 3 differs from 2, as the smaller twofold symmetry-related, round α-CD prefers an exclusion complex with the twofold disordered TRM-H+ sites. In the orthorhombic P21212 lattice, α-CDs are packed in a channel-type structure, where the column-like cavity is occupied by disordered water sites. DFT results indicate that ß-CD remains elliptical to suitably accommodate TRM, yielding an energetically favorable inclusion complex, which is significantly contributed by the ß-CD deformation, and the inclusion complex of α-CD with the TRM aminoethyl side chain is also energetically favorable compared to the exclusion mode. This study suggests the CD implications for food safety and drug/bioactive formulation and delivery.

Tyramine beta hydroxylase-mediated octopamine synthesis pathway in Litopenaeus vannamei under thermal, salinity, and Vibrio alginolyticus infection stress.

Stress responses impact the immune systems, growth, and reproduction of aquatic organisms. Neuroendocrine regulation involving biogenic amines, including octopamine (OA), plays a pivotal role in maintaining physiological balance during stress. This study focuses on the synthesis pathway of OA, particularly the role of tyramine beta hydroxylase (TBH), in Litopenaeus vannamei under stress. TBH catalyzes the conversion of tyramine to OA, a process critical for physiological responses. The present study demonstrated LvTBH at the protein level under different stress conditions during acute (0.5, 1, 2 h) and chronic stress (24, 72, 168 h) periods. LvTBH increased in thoracic ganglia within 2 h under hyperthermal stress, accompanied by elevated OA levels. Conversely, LvTBH decreased in the brain and circumesophageal connective tissues during acute and chronic hypothermal stress. Additionally, LvTBH increased in the brain and circumesophageal connective tissues under acute infection stress, coinciding with elevated OA levels. These findings collectively contribute to a more intricate understanding of the neuroendocrine dynamics within L. vannamei under stress, underscoring the role of TBH in orchestrating responses crucial for adaptation.

Enzymatically mediated fluorescent copper nanocluster generation for tyramine determination.

This work details the enzymatic generation of fluorescence nanomaterials and the use of this optical signal as the analytical parameter for the quantification of the substrate. More specifically, fluorescent copper nanoclusters have been obtained during the enzymatic reaction of tyramine oxidase and tyramine in the presence of Cu(II); the fluorescence intensity being proportional to the concentration of tyramine. The nanoclusters obtained show fluorescence at 445 nm by being excited at 320 nm and have been characterized by TEM, EDX, and XPS. The formation mechanism has also been studied, suggesting that under the optimal conditions (0.1 M MES buffer and pH = 6), the formation of the nanoclusters is due to the reducing properties of the product of the enzymatic reaction (p-hydroxybenzaldehyde) in MES buffer. The method shows a linear relationship with the concentration of tyramine in the range from 1.0·10-5 to 2.5·10-4 M, a RSD of 3% (n = 5) and a LOD of 6.3·10-6 M. The method has been applied to the determination of tyramine in sausage with good results.

Portable colorimetric enzymatic disposable biosensor for histamine and simultaneous histamine/tyramine determination using a smartphone.

Tyramine oxidase (TAO), peroxidase (HRP), and Amplex Red (AR) have been immobilized on cellulose to obtain disposable biosensors for the determination of histamine. During the enzymatic reaction, AR is oxidized and a pink spot is obtained. Using a smartphone and measuring the G (green) color coordinate, histamine can be determined in the presence of other biogenic amines (putrescine and cadaverine) in concentrations ranging from 2·10-5 M to 5·10-4 M with a 7.5·10-6 M limit of detection (LoD). Despite tyramine interference, experimental conditions are provided which allow rapid and simple histamine and simultaneous histamine/tyramine (semi)quantitative determination in mixtures. Finally, tyramine and histamine were determined in a tuna extract with good results (compared to the reference HPLC-MS method). The methodology can also be applied in solution allowing histamine (and simultaneous histamine/tyramine) determination with a lower LoD (1.8·10-7 M) and a similar selectivity.

An ultrasensitive ELISA to assay femtomolar level SARS-CoV-2 antigen based on specific peptide and tyramine signal amplification.

The SARS-CoV-2 spreading rapidly has aroused catastrophic public healthcare issues and economy crisis worldwide. It plays predominant role to rapidly and accurately diagnose the virus for effective prevention and treatment. As an abundant transmembrane protein, spike protein (SP) is one of the most valuable antigenic biomarkers for diagnosis of COVID-19. Herein a phage expression of WNLDLSQWLPPM peptide specific to SARS-CoV-2 SP was screened. Molecular docking revealed that the isolated peptide binds to major antigenic epitope locating at S2 subunit with hydrogen bonding. Taking the specific peptide as antigen sensing probe and tyramine signal amplification (TSA), an ultrasensitive "peptide-antigen-antibody" ELISA (p-ELISA) was explored, by which the limit of detection (LOD) was 14 fM and 2.8 fM SARS-CoV-2 SP antigen for first TSA and secondary TSA, respectively. Compared with the LOD by the p-ELISA by direct mode, the sensitivity with 2nd TSA enhanced 100 times. Further, the proposed p-ELISA method can detect SARS-CoV-2 pseudoviruses down to 10 and 3 TCID50/mL spiked in healthy nasal swab sample with 1st TSA and 2nd TSA, separately. Thus, the proposed p-ELISA method with TSA is expected to be a promising ultrasensitive tool for rapidly detecting SARS-CoV-2 antigen to help control the infectious disease.

Marination increased tyramine levels in rainbow trout fillet strips packaged under modified atmosphere.

Marinades are increasingly used to manufacture raw fish products. In corresponding meats, marinating is known to have a major effect on the composition of the microbiome, but the effect of marinating on fish is not known as well. This knowledge gap prompted our study of the microbial ecology and amine formation in marinated and unmarinated modified atmosphere commercially packaged rainbow trout fillet strips. According to our findings, marination increased the maximum concentrations (7-8 log CFU/g) of psychrotrophic bacteria by one logarithmic unit and led to 5 times higher average tyramine concentrations than the corresponding unmarinated product. Instead, trimethylamine concentrations were 30 times higher in the unmarinated product than those in the marinated one. According to the 16 S rRNA sequence analyses, lactic acid bacteria (LAB) predominated in the marinated strips one day after the use-by date, whereas in the unmarinated strips Fusobacteriaceae and LAB were the dominating taxa. Based on the culture-dependent analysis, Latilactobacillus fuchuensis was the prevailing LAB in both products. Since the subset of L. fuchuensis strains tested was able to produce tyramine in vitro, we hypothesise that the use of the acidic marinade activated the production of tyrosine-decarboxylating enzymes in L. fuchuensis and led to the increased tyramine concentrations.

In situ enzymatic generation of Au/Pt nanoparticles as an analytical photometric system: proof of concept determination of tyramine.

In situ enzymatic generation of bimetallic nanoparticles, mainly Au/Pt, overcomes the drawbacks (continuous absorbance drift, modest LOQ, and long-time reaction) observed when AuNP alone are produced. In this study, Au/Pt nanoparticles have been characterized by EDS, XPS, and HRTEM images using the enzymatic determination of tyramine with tyramine oxidase (TAO) as a model. Under experimental conditions, the Au/Pt NPs show an absorption maximum at 580 nm which can be related to the concentration of tyramine in the range 1.0 × 10-6M to 2.5 × 10-4M with a RSD of 3.4% (n = 5, using 5 × 10-6M tyramine). The Au/Pt system enables low LOQ (1.0 × 10-6 M), high reduction of the absorbance drift, and a significant shortening of the reaction time (i.e., from 30 to 2 min for a [tyramine] = 1 × 10-4M); additionally, a better selectivity is also obtained. The method has been applied to tyramine determination in cured cheese and no significant differences were obtained compared to a reference method (HRP:TMB). The effect of Pt(II) seems to involve the previous reduction of Au(III) to Au(I) and NP generation from this oxidation state. Finally, a three-step (nucleation-growth-aggregation) kinetic model for the generation of NPs is proposed; this has enabled us to obtain a mathematical equation which explains the experimentally observed variation of the absorbance with time.

Tectomer-Mediated Optical Nanosensors for Tyramine Determination.

The development of optical sensors for in situ testing has become of great interest in the rapid diagnostics industry. We report here the development of simple, low-cost optical nanosensors for the semi-quantitative detection or naked-eye detection of tyramine (a biogenic amine whose production is commonly associated with food spoilage) when coupled to Au(III)/tectomer films deposited on polylactic acid (PLA) supports. Tectomers are two-dimensional oligoglycine self-assemblies, whose terminal amino groups enable both the immobilization of Au(III) and its adhesion to PLA. Upon exposure to tyramine, a non-enzymatic redox reaction takes place in which Au(III) in the tectomer matrix is reduced by tyramine to gold nanoparticles, whose reddish-purple color depends on the tyramine concentration and can be identified by measuring the RGB coordinates (Red-Green-Blue coordinates) using a smartphone color recognition app. Moreover, a more accurate quantification of tyramine in the range from 0.048 to 10 µM could be performed by measuring the reflectance of the sensing layers and the absorbance of the characteristic 550 nm plasmon band of the gold nanoparticles. The relative standard deviation (RSD) of the method was 4.2% (n = 5) with a limit of detection (LOD) of 0.014 µM. A remarkable selectivity was achieved for tyramine detection in the presence of other biogenic amines, especially histamine. This methodology, based on the optical properties of Au(III)/tectomer hybrid coatings, is promising for its application in food quality control and smart food packaging.

Chondroitin Sulfate-Tyramine-Based Hydrogels for Cartilage Tissue Repair.

The degradation of cartilage, due to trauma, mechanical load or diseases, results in abundant loss of extracellular matrix (ECM) integrity and development of osteoarthritis (OA). Chondroitin sulfate (CS) is a member of the highly sulfated glycosaminoglycans (GAGs) and a primary component of cartilage tissue ECM. In this study, we aimed to investigate the effect of mechanical load on the chondrogenic differentiation of bone marrow mesenchymal stem cells (BM-MCSs) encapsulated into CS-tyramine-gelatin (CS-Tyr/Gel) hydrogel in order to evaluate the suitability of this composite for OA cartilage regeneration studies in vitro. The CS-Tyr/Gel/BM-MSCs composite showed excellent biointegration on cartilage explants. The applied mild mechanical load stimulated the chondrogenic differentiation of BM-MSCs in CS-Tyr/Gel hydrogel (immunohistochemical collagen II staining). However, the stronger mechanical load had a negative effect on the human OA cartilage explants evaluated by the higher release of ECM components, such as the cartilage oligomeric matrix protein (COMP) and GAGs, compared to the not-compressed explants. Finally, the application of the CS-Tyr/Gel/BM-MSCs composite on the top of the OA cartilage explants decreased the release of COMP and GAGs from the cartilage explants. Data suggest that the CS-Tyr/Gel/BM-MSCs composite can protect the OA cartilage explants from the damaging effects of external mechanical stimuli. Therefore, it can be used for investigation of OA cartilage regenerative potential and mechanisms under the mechanical load in vitro with further perspectives of therapeutic application in vivo.

The Effects of Mechanical Load on Chondrogenic Responses of Bone Marrow Mesenchymal Stem Cells and Chondrocytes Encapsulated in Chondroitin Sulfate-Based Hydrogel.

Articular cartilage is vulnerable to mechanical overload and has limited ability to restore lesions, which leads to the development of chronic diseases such as osteoarthritis (OA). In this study, the chondrogenic responses of human bone marrow mesenchymal stem cells (BMMSCs) and OA cartilage-derived chondrocytes in 3D chondroitin sulfate-tyramine/gelatin (CS-Tyr)/Gel) hydrogels with or without experimental mechanical load have been investigated. Chondrocytes were smaller in size, had slower proliferation rate and higher level of intracellular calcium (iCa2+) compared to BMMSCs. Under 3D chondrogenic conditions in CS-Tyr/Gel with or without TGF-ß3, chondrocytes more intensively secreted cartilage oligomeric matrix protein (COMP) and expressed collagen type II (COL2A1) and aggrecan (ACAN) genes but were more susceptible to mechanical load compared to BMMSCs. ICa2+ was more stably controlled in CS-Tyr/Gel/BMMSCs than in CS-Tyr/Gel/chondrocytes ones, through the expression of L-type channel subunit CaV1.2 (CACNA1C) and Serca2 pump (ATP2A2) genes, and their balance was kept more stable. Due to the lower susceptibility to mechanical load, BMMSCs in CS-Tyr/Gel hydrogel may have an advantage over chondrocytes in application for cartilage regeneration purposes. The mechanical overload related cartilage damage in vivo and the vague regenerative processes of OA chondrocytes might be associated to the inefficient control of iCa2+ regulating channels.

Histamine and Tyramine in Chihuahua Cheeses during Shelf Life: Association with the Presence of tdc and hdc Genes.

Cheese is a product of animal origin with a high nutritional value, and it is one of the most consumed dairy foods in Mexico. In addition, Chihuahua cheese is the most consumed matured cheese in Mexico. In the production process of Chihuahua cheese, maturation is carried out by adding acid lactic microorganisms, mainly of the Lactococcus genus and, in some cases, also the Streptococcus and Lactobacillus genus. As part of the metabolism of fermenting microorganisms, biogenic amines can develop in matured foods, which result from the activity of amino decarboxylase enzymes. In cheeses, histamine and tyramine are the main amines that are formed, and the consumption of these represents a great risk to the health of consumers. In this work, the presence of biogenic amines (histamine and tyramine) was determined by HPLC at different times of the shelf life of Chihuahua cheeses. In addition, the presence of genes hdc and tdc that code for the enzymes responsible for the synthesis of these compounds (histidine and tyrosine decarboxylase, or HDC and TDC) was determined by molecular techniques. A significant correlation was observed between the presence of both histamine and tyramine at the end of shelf life with the presence of genes that code for the enzymes responsible for their synthesis.

Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder.

BACKGROUND: Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). METHODS: This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. RESULTS: All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. CONCLUSION: These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.

Elusive amines: migraine depends on biochemical abnormalities.

The pathogenesis of migraine, as well as cluster headache (CH), is yet a debated question. In this review, we discuss the possible role of tyrosine and tryptophan metabolism in the pathogenesis of primary headaches, including the abnormalities in the synthesis of neurotransmitters. High level of dopamine, low level of norepinephrine, and very elevated levels of octopamine and synephrine were found in the plasma of episodic migraine without aura. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward increased decarboxylase and reduced hydroxylase enzyme activities, favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity. In addition, we present biochemical studies performed in chronic migraine (CM) and chronic tension-type headache patients (CTTH) to verify if the same anomalies are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine-related metabolites are present only in CM patients while tryptamine plasma levels were found significantly lower in both CM and CTTH patients. Because of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold.