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Author(s): Mengyu Li [sup.1] , Man Ki Kwok [sup.1] , Shirley Siu Ming Fong [sup.1] , Catherine Mary Schooling [sup.1] [sup.2] Author Affiliations: (1) School of Public Health, Li Ka [...], Background/objectives Tryptophan is an essential amino acid that must be obtained from dietary items, such as dairy products, eggs, nuts, legumes, and grains, which are rich in tryptophan. It has also been suggested as a dietary supplement to improve mental health. Observationally plasma tryptophan is inversely associated with ischemic heart disease (IHD), however, its main metabolites, serotonin, and kynurenine are positively associated with IHD, which makes the effects of tryptophan difficult to infer. This study aimed to obtain less-confounded estimates of the associations of tryptophan and physiologically related factors (serotonin and kynurenine) with IHD, its risk factors and depression. Subjects/methods We used a two-sample Mendelian Randomization study design. We used genetic instruments independently associated with tryptophan, serotonin, and kynurenine metabolites applied to a meta-analysis of the UK Biobank SOFT CAD study with the CARDIoGRAMplusC4D consortium (cases n [less than or equal to] 76,014 and controls n [less than or equal to] 264,785), and other consortia for risk factors including diabetes, lipids, and blood pressure, as well as for depression. We combined genetic variant-specific estimates using inverse variance weighting, with MR-Egger, the weighted median and MR-PRESSO as sensitivity analyses. Results Tryptophan and serotonin were not associated with IHD. Kynurenine was nominally and positively associated with IHD (odds ratio 1.57 per standard deviation, 95% confidence interval 1.05-2.33) but not after correction for multiple comparisons. Associations with IHD risk factors and depression were null. Conclusions We cannot exclude the possibility that one of the main metabolites of tryptophan, kynurenine, might be positively associated with IHD. Further studies are needed to confirm any association and underlying mechanism.

Introduction The cardiovascular responses produced by serotonin (5-hydroxytryptamine; 5-HT) involve complex interactions with different receptors at several levels. These include the central nervous system, autonomic ganglia and postganglionic nerve endings, [...], Serotonin (5-hydroxytryptamine; 5-HT) inhibits the rat cardioaccelerator sympathetic outflow by 5-[HT.sub.1/5B]/1D/5 receptors. Because chronic blockade of sympatho-excitatory 5-[HT.sub.2] receptors is beneficial in several cardiovascular pathologies, this study investigated whether sarpogrelate (a 5-[HT.sub.2] receptor antagonist) alters the pharmacological profile of the above sympathoinhibition. Rats were pretreated for 2 weeks with sarpogrelate in drinking water (30 mg/kg per day; sarpogrelate-treated group) or equivalent volumes of drinking water (control group). Animals were pithed and prepared for spinal stimulation ([C.sub.7]-[T.sub.1] cardioaccelerator sympathetic outflow or for intravenous (i.v.) bolus injections of noradrenaline. Both procedures produced tachycardic responses remaining unaltered after saline. Continuous i.v. infusions of 5-HT induced a cardiac sympatho- inhibition that was mimicked by the 5-HT receptor agonists 5- carboxamidotryptamine (5-CT; 5-[HT.sub.1/5A]), CP 93,129 (5-[HT.sub.1/5B]), or PNU142633 (5-[H.sub.T1D]), but not by indorenate (5- [HT.sub.1/5A]) in both groups; whereas LY344864 (5-[H.sub.T1F]) mimicked 5-HT only in sarpogrelate-treated rats. In sarpogrelate-treated animals, i.v. GR 127935 (310 [micro]g/kg; 5- [HT.sub.1/5B/1D/1F] receptor antagonist) attenuated 5-CT-induced sympatho-inhibition and abolished LY344864-induced sympatho-inhibition; while GR 127935 plus SB 699551 (1 mg/kg; 5-[HT.sub.5A] receptor antagonist) abolished 5-CT-induced inhibition. These results confirm the cardiac sympatho-inhibitory role of 5-[HT.sub.1/5B], 5-[HT.sub.1D], and 5-[HT.sub.5A] receptors in both groups; nevertheless, sarpogrelate treatment specifically unmasked a cardiac sympathoinhibition mediated by 5-[HT.sub.1F] receptors. Key words: 5-HTjp receptor, 5-[HT.sub.2] receptor, cardiac sympatho-inhibition, sarpogrelate, tachycardia. La serotonine (5-hydroxytryptamine; 5-HT) inhibe les efferences sympathiques cardioacceleratrices de rat par l'intermediaire des recepteurs 5-[HT.sub.1/5B]/1D/5. Comme le blocage a long terme des recepteurs 5-[HT.sub.2], excitateurs des voies sympathiques, est avantageux dans plusieurs pathologies cardiovasculaires, ces travaux visaient a etudier si le sarpogrelate (un inhibiteur des recepteurs 5-[HT.sub.2]) modifie le profil pharmacologique de l'inhibition sympathique par la 5-HT. Nous avons administre au prealable aux rats du sarpogrelate dans l'eau potable (30 mg/kg par jour; groupe sarpogrelate) ou des volumes equivalents d'eau potable (groupe temoin) pendant 2 semaines. Nous avons demedule les animaux et nous les avons prepares a une stimulation spinale ([C.sub.7]-[T.sub.1]) des efferences sympathiques cardioacceleratrices, ou a l'injection intraveineuse (i.v.) de bolus d'adrenaline. Les deux interventions ont entraine des reactions de tachycardie qui n'etaient pas modifiees apres l'administration de solution saline. La perfusion i.v. de 5-HT en continu engendrait une inhibition sympathique cardiaque, que l'on pouvait mimer dans les deux groupes a l'aide de certains agonistes des recepteurs 5-HT comme la 5-carboxamidotryptamine (5-CT; 5-[HT.sub.1/5A]), le CP 93,129 (5-[HT.sub.1/5B]) ou le PNU 142633 (5- [HT.sub.1D]), mais pas par l'indorenate (5- [HT.sub.1/5A]). Pour sa part, le LY344864 (5-[HT.sub.1F]) permettait de mimer les effets de la 5-HT uniquement dans le groupe sarpogrelate. Dans le groupe sarpogrelate, l'administration i.v. de GR 127935 (310 [micro]g/kg; antagoniste des recepteurs 5- [HT.sub.1/5B/1D/1F]) entrainait une attenuation de l'inhibition sympathique engendree par la 5-CT ainsi qu'une abolition de l'inhibition sympathique engendree par le LY344864. Pour sa part, l'association du GR 127935 avec le SB 699551 (1 mg/kg; antagoniste des recepteurs 5- [HT.sub.5A]) entrainait une abolition de l'inhibition engendree par la 5-CT. Ces resultats viennent confirmer que les recepteurs 5- [HT.sub.1/5B], 5-[HT.sub.1D], et 5-[HT.sub.5A] jouent un role dans l'inhibition de la stimulation sympathique du coeur. Neanmoins, l'administration de sarpogrelate a revele specifiquement la presence d'une inhibition de la stimulation sympathique du coeur mediee par les recepteurs 5- [HT.sub.1F]. [Traduit par la Redaction] Mots-cles: recepteurs 5-[HT.sub.1F], recepteurs 5-[HT.sub.2], inhibition de la stimulation sympathique du coeur, sarpogrelate, tachycardie.

Introduction Atypical antipsychotics (AATPs) are second-generation antipsychotics that are currently used to treat a variety of psychiatric conditions, including schizophrenia, bipolar disorder, depression, and autism (1). Despite their documented efficacy [...], Atypical antipsychotics such as olanzapine often induce excessive weight gain and type 2 diabetes. However, the mechanisms underlying these drug-induced metabolic perturbations remain poorly understood. Here, we used an experimental model that reproduces olanzapine-induced hyperphagia and obesity in female C57BL/6 mice. We found that olanzapine treatment acutely increased food intake, impaired glucose tolerance, and altered physical activity and energy expenditure in mice. Furthermore, olanzapine-induced hyperphagia and weight gain were blunted in mice lacking the serotonin 2C receptor (HTR2C). Finally, we showed that treatment with the HTR2C-specific agonist lorcaserin suppressed olanzapine-induced hyperphagia and weight gain. Lorcaserin treatment also improved glucose tolerance in olanzapine-fed mice. Collectively, our studies suggest that olanzapine exerts some of its untoward metabolic effects via antagonism of HTR2C.

Introduction Pain is an adaptive warning signal under physiological conditions, but it also causes a lot of suffering during various pathological states. Pain is a complex phenomenon with many components. [...], Pain is fundamentally unpleasant and induces a negative affective state. The affective component of pain is mediated by circuits that are distinct from those mediating the sensory-discriminative component. Here, we have investigated the role of prostaglandins in the affective dimension of pain using a rodent pain assay based on conditioned place aversion to formalin injection, an inflammatory noxious stimulus. We found that place aversion induced by inflammatory pain depends on prostaglandin E2 that is synthesized by cyclooxygenase 2 in neural cells. Further, mice lacking the prostaglandin E2 receptor [EP.sub.3] selectively on serotonergic cells or selectively in the area of the dorsal raphe nucleus failed to form an aversion to formalininduced pain, as did mice lacking the serotonin transporter. Chemogenetic manipulations revealed that [EP.sub.3] receptor activation elicited conditioned place aversion to pain via inhibition of serotonergic neurons. In contrast to their role in inflammatory pain aversion, [EP.sub.3] receptors on serotonergic cells were dispensable for acute nociceptive behaviors and for aversion induced by thermal pain or a k opioid receptor agonist. Collectively, our findings show that prostaglandin-mediated modulation of serotonergic transmission controls the affective component of inflammatory pain.

Hepatic transporters and drug metabolizing enzymes (DMEs) play important roles in the pharmacological effects and (or) side-effects of many drugs, and are regulated by several mediators, including neurotransmitters. This work aimed to investigate whether serum levels of 5-hydroxytryptamine (5-HT) affected the expression of hepatic transporters or DMEs. The expression of hepatic transporters was assessed using the Western-blot technique in a 2,4,6-trinitrobenzenesulfonic-acid-induced rat model of post-infectious irritable bowel syndrome (PI-IBS), in which serum levels of 5-HT were significantly elevated. To further clarify the underlying mechanism, the 5-HT precursor 5-hydroxytryptophan (5-HTP) and the 5-HT depleting agent parachlorophenylalanine (pCPA) were applied to adjust serum levels of 5-HT. Serum levels of 5-HT were measured using LC-MS/MS; the expression of hepatic transporters, DMEs, and nuclear receptors were examined by Western-blot technique. Our results showed that in PI-IBS rats the expression of multidrug resistance protein 2 (Mrp2) was significantly decreased, while colonic enterochromaffin cell density and serum levels of 5-HT were all significantly increased. Moreover, 5-HTP treatment significantly increased serum levels of 5-HT and decreased the expression of Mrp2 and glycoprotein P (P-gp), whereas treatment with pCPA markedly decreased serum levels of 5-HT and increased the expression of Mrp2 and P-gp. Our results indicated that serum 5-HT regulates the expression of Mrp2 and P-gp, and the underlying mechanism may be related to the altered expression of the nuclear receptor constitutive androstane receptor (CAR). Key words: 5-HT, hepatic transporters, metabolic enzymes, liver, 5-HTP. Les proteines de transport hepatiques et les enzymes du metabolisme des medicaments participent largement aux effets pharmacologiques benefiques ou indesirables de beaucoup de medicaments. Les effets de ces facteurs pourraient etre regules par plusieurs mediateurs, dont les neurotransmetteurs. La presente etude vise a determiner si les taux seriques de serotonine (5-HT) jouent un role dans l'expression des proteines de transport hepatiques et des enzymes du metabolisme des medicaments. L'expression des proteines de transport hepatiques a ete evaluee au moyen d'une technique de Western-blot appliquee aun modele dans lequel les taux seriques de 5-HT sont tres eleves : le modele de syndrome du colon irritable post-infectieux induit par l'acide 2,4,6-trinitrobenzene sulfonique (TNBS) chez le rat. En vue de mieux comprendre le mecanisme sous-jacent, le 5-hydroxytryptophane (ou 5-HTP, precurseur de la 5-HT) et la para-chlorophenylanlanine (ou pCPA, un inhibiteur de la synthese de la 5-HT) ont ete administres afin de faire varier les taux seriques de 5-HT. Ces taux ont ete mesures et les expressions des proteines de transport hepatiques, des enzymes du metabolisme hepatiques ainsi que des recepteurs nucleaires ont ete evaluees par Western-blot. Les resultats ont montre que l'expression du transporteur Mrp2 (' multidrug resistance protein 2 ') diminuait nettement, tandis que la densite des cellules enterochromaffines du colon et les taux seriques de 5-HT augmentaient nettement chez les rats presentant un syndrome du colon irritable post-infectieux. De plus, le traitement par le 5-HTP entrainait une diminution marquee de l'expression du transporteur Mrp2 et de la glycoproteine P (ou P-gp), alors que le traitement par la pCPA entrainait une diminution marquee des taux seriques de 5-HT associee a une augmentation de l'expression du transporteur Mrp2 et de la P-gp. Nos resultats indiquent que les taux seriques de 5-HT pourraient reguler l'expression du transporteur Mrp2 et de la P-gp, et que le mecanisme sous-jacent pourrait etre relie a la modification de l'expression du recepteur nucleaire CAR (recepteur constitutif a l'androstane). [Traduit par la Redaction] Mots-cles: 5-HT, transporteurs hepatiques, enzymes metaboliques, foie, 5-HTP., Introduction Elimination of a drug from the body is complex and involves both biotransformation and the cellular uptake or excretion of the products via various transporter-mediated processes (Ueyama et al. [...]

Introduction Elimination of a drug from the body is complex and involves both biotransformation and the cellular uptake or excretion of the products via various transporter-mediated processes (Ueyama et al. [...], Hepatic transporters and drug metabolizing enzymes (DMEs) play important roles in the pharmacological effects and (or) side-effects of many drugs, and are regulated by several mediators, including neurotransmitters. This work aimed to investigate whether serum levels of 5-hydroxytryptamine (5-HT) affected the expression of hepatic transporters or DMEs. The expression of hepatic transporters was assessed using the Western-blot technique in a 2,4,6-trinitrobenzenesulfonic -acid-induced rat model of post-infectious irritable bowel syndrome (PI-IBS), in which serum levels of 5-HT were significantly elevated. To further clarify the underlying mechanism, the 5-HT precursor 5-hydroxytryptophan (5-HTP) and the 5-HT depleting agent parachlorophenylalanine (pCPA) were applied to adjust serum levels of 5-HT. Serum levels of 5-HT were measured using LC-MS/MS; the expression of hepatic transporters, DMEs, and nuclear receptors were examined by Western -blot technique. Our results showed that in PI-IBS rats the expression of multidrug resistance protein 2 (Mrp2) was significantly decreased, while colonic enterochromaffin cell density and serum levels of 5-HT were all significantly increased. Moreover, 5-HTP treatment significantly increased serum levels of 5-HT and decreased the expression of Mrp2 and glycoprotein P (P-gp), whereas treatment with pCPA markedly decreased serum levels of 5-HT and increased the expression of Mrp2 and P-gp. Our results indicated that serum 5-HT regulates the expression of Mrp2 and P-gp, and the underlying mechanism may be related to the altered expression of the nuclear receptor constitutive androstane receptor (CAR). Key words: 5-HT, hepatic transporters, metabolic enzymes, liver, 5-HTP. Les proteines de transport hepatiques et les enzymes du metabolisme des medicaments participent largement aux effets pharmacologiques benefiques ou indesirables de beaucoup de medicaments. Les effets de ces facteurs pourraient etre regules par plusieurs mediateurs, dont les neurotransmetteurs. La presente etude vise a determiner si les taux seriques de serotonine (5-HT) jouent un role dans l'expression des proteines de transport hepatiques et des enzymes du metabolisme des medicaments. L'expression des proteines de transport hepatiques a ete evaluee au moyen d'une technique de Western-blot appliquee aun modele dans lequel les taux seriques de 5-HT sont tres eleves : le modele de syndrome du colon irritable post-infectieux induit par l'acide 2,4,6-trinitrobenzene sulfonique (TNBS) chez le rat. En vue de mieux comprendre le mecanisme sous-jacent, le 5-hydroxytryptophane (ou 5-HTP, precurseur de la 5-HT) et la para-chlorophenylanlanine (ou pCPA, un inhibiteur de la synthese de la 5-HT) ont ete administres afin de faire varier les taux seriques de 5-HT. Ces taux ont ete mesures et les expressions des proteines de transport hepatiques, des enzymes du metabolisme hepatiques ainsi que des recepteurs nucleaires ont ete evaluees par Western-blot. Les resultats ont montre que l'expression du transporteur Mrp2 (<< multidrug resistance protein 2 >>) diminuait nettement, tandis que la densite des cellules enterochromaffines du colon et les taux seriques de 5-HT augmentaient nettement chez les rats presentant un syndrome du colon irritable post-infectieux. De plus, le traitement par le 5-HTP entrainait une diminution marquee de l'expression du transporteur Mrp2 et de la glycoproteine P (ou P-gp), alors que le traitement par la pCPA entrainait une diminution marquee des taux seriques de 5-HT associee a une augmentation de l'expression du transporteur Mrp2 et de la P-gp. Nos resultats indiquent que les taux seriques de 5-HT pourraient reguler l'expression du transporteur Mrp2 et de la P-gp, et que le mecanisme sous-jacent pourrait etre relie a la modification de l'expression du recepteur nucleaire CAR (recepteur constitutif a l'androstane). [Traduit par la Redaction] Mots-cles: 5-HT, transporteurs hepatiques, enzymes metaboliques, foie, 5-HTP.