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Andrea Hembre Ulsund, Marie Dahl, Thomas M Frimurer, Ornella Manfra, Thue W Schwartz, Finn Olav Levy, Kjetil Wessel Andressen
According to early models of GPCR signaling, G proteins only interact with activated receptors. However, some GPCRs were shown to assemble with G proteins before receptor activation, in accordance with more recent models. Previously, we found that the 5-HT7 receptor, as opposed to the 5-HT4 receptor, was preassociated with Gs , but the molecular determinants for this interaction are still elusive. In a series of chimeric 5-HT7 receptors with intracellular segments from 5-HT4 , we determined the receptor-G protein interaction by performing antibody-immobilized fluorescence recovery after photobleaching and fluorescence resonance energy transfer...
December 3, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Julia Maxwell, Scott D Gleason, Julie Falcone, Kjell Svensson, Olivia M Balcer, Xia Li, Jeffrey M Witkin
5-HT7 receptors have been suggested to play a role in the regulation of psychiatric disorders. The experimental literature however is not fully consistent on this possibility. Two selective 5-HT7 receptor antagonists, DR-4004 and SB-269970, were evaluated in mouse models used to detect drugs used to treat anxiety, depression, or schizophrenia. A 5-HT-induced hypothermia assay was used to define the doses of DR-4004 and SB-269970 predicted to impact 5-HT7 receptors in the brain in vivo. 5-HT induced hypothermia in wildtype mice by either i...
November 21, 2018: Behavioural Brain Research
Cristina López, Miriam Gómez-Roso, José Ángel García-Pedraza, María Luisa Martín, Asunción Morán, Mónica García-Domingo
Although depression and cardiovascular diseases are related, the role of antidepressants, as fluoxetine (increasing serotonin levels), within cardiac regulation remains unclear. We aimed to determine whether fluoxetine modifies the pharmacological profile of serotonergic influence on vagal cardiac outflow. Rats were treated with fluoxetine (10 mg/; p.o.) for 14 days or equivalent volumes of drinking water (control group); then, they were pithed and prepared for vagal stimulation. Bradycardic responses were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or i...
November 21, 2018: Canadian Journal of Physiology and Pharmacology
Stevie Margaret Lockwood, Kirsty Bannister, Anthony H Dickenson
Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play...
November 21, 2018: Journal of Neurophysiology
Xenia Gonda, Samata R Sharma, Frank I Tarazi
Vortioxetine is a novel antidepressant drug approved for the treatment of major depressive disorder (MDD) in adults. It is formulated into tablets and has a dose range of 5-20 mg. The recommended starting dose is 10 mg administered orally once daily without the need for food. Areas covered: This review focuses on the preclinical and clinical discovery of vortioxetine. It analyzes the pharmacological, neurochemical, and behavioral mechanisms of the medication and how these contribute to its potential therapeutic advantages as described in published preclinical and clinical studies and product labels...
November 20, 2018: Expert Opinion on Drug Discovery
Diogo A Fonseca, Cristina Teixeira, Félix Carvalho, Eduarda Fernandes, Pedro E Antunes, Manuel J Antunes, Maria Dulce Cotrim
3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") is a popular recreational drug of abuse. In addition to its characteristic psychotropic effects, important cardiovascular effects have been described such as increased blood pressure and heart rate. MDMA was previously shown to behave as a partial agonist on 5-hydroxytryptamine (5-HT) receptors in the human internal thoracic artery in vitro, involving the 5-HT2A subtype. Here, we studied the interaction of MDMA (400, 800 and 1600 μM) with the following 5-HT receptor agonists: 5-carboxamidotryptamine (5-CT, full agonist for the 5-HT1 , 5-HT2 , 5-HT5 , 5-HT6 and 5-HT7 receptors) and sumatriptan (selective 5-HT1B/1D receptors agonist)...
November 15, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Karolina Pytka, Monika Głuch-Lutwin, Elżbieta Żmudzka, Kinga Sałaciak, Agata Siwek, Katarzyna Niemczyk, Maria Walczak, Magdalena Smolik, Adrian Olczyk, Adam Gałuszka, Jarosław Śmieja, Barbara Filipek, Jacek Sapa, Marcin Kołaczkowski, Katarzyna Pańczyk, Anna Waszkielewicz, Henryk Marona
Numerous studies have proven that both stimulation and blockade of 5-HT1A and the blockade of 5-HT7 receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic-like activity, as well as the possible mechanism of action of 1-[(2,5-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT1A and 5-HT7 receptors and antidepressant-like properties...
2018: Frontiers in Pharmacology
Justyna Kalinowska-Tłuścik, Agata Piaskowska, Marcin Kołaczkowski
Nowadays, a search for antagonists co-acting on serotonin receptor subtypes 6 and 7 (5-HT6 R and 5-HT7 R, respectively) is of great interest due to the increasing number of patients suffering from dementia and related behavioural and psychological symptoms. The X-ray crystal structures of four promising multifunctional ligands in the hydrochloride forms were determined, namely 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-methylbenzenesulfonamido)propyl]piperidin-1-ium chloride, C22 H27 FN3 O3 S+ ·Cl- , (I), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C25 H28 F2 N3 O3 S2 + ·Cl- , (II), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(6-fluorobenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C24 H26 ClFN3 O3 S2 + ·Cl- , (III), and 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-chloro-4-fluorobenzenesulfonamido)propyl]piperidin-1-ium chloride, C21 H22 ClF2 N3 O3 S2 + ·Cl- , (IV)...
November 1, 2018: Acta Crystallographica. Section C, Structural Chemistry
Raphael R Perim, Daryl P Fields, Gordon S Mitchell
KEY POINTS SUMMARY: Concurrent 5-HT2A (Q pathway) and 5-HT7 (S pathway) serotonin receptor activation cancels phrenic motor facilitation due to mutual cross-talk inhibition Spinal PKCδ or PKA inhibition restores phrenic motor facilitation with concurrent Q and S pathway activation, demonstrating a key role for these kinases in cross-talk inhibition Spinal PKCδ inhibition enhances adenosine-dependent severe AIH-induced pLTF (S pathway), consistent with relief of cross-talk inhibition...
November 1, 2018: Journal of Physiology
Lara Costa, Lara Maria Sardone, Carmela Maria Bonaccorso, Simona D'Antoni, Michela Spatuzza, Walter Gulisano, Maria Rosaria Tropea, Daniela Puzzo, Marcello Leopoldo, Enza Lacivita, Maria Vincenza Catania, Lucia Ciranna
We have previously demonstrated that activation of serotonin 5-HT7 receptors (5-HT7 R) reverses metabotropic glutamate receptor-mediated long term depression (mGluR-LTD) in the hippocampus of wild-type (WT) and Fmr1 Knockout (KO) mice, a model of Fragile X Syndrome (FXS) in which mGluR-LTD is abnormally enhanced. Here, we have investigated intracellular mechanisms underlying the effect of 5-HT7 R activation using patch clamp on hippocampal slices. Furthermore, we have tested whether in vivo administration of LP-211, a selective 5-HT7 R agonist, can rescue learning and behavior in Fmr1 KO mice...
2018: Frontiers in Molecular Neuroscience
Daniele Vigli, Laura Rusconi, Daniela Valenti, Paolo La Montanara, Livia Cosentino, Enza Lacivita, Marcello Leopoldo, Elena Amendola, Cornelius Gross, Nicoletta Landsberger, Giovanni Laviola, Charlotte Kilstrup-Nielsen, Rosa A Vacca, Bianca De Filippis
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause CDKL5 Deficiency Disorder (CDD), a rare neurodevelopmental syndrome characterized by severe behavioural and physiological symptoms. No cure is available for CDD. CDKL5 is a kinase that is abundantly expressed in the brain and plays a critical role in neurodevelopmental processes, such as neuronal morphogenesis and plasticity. This study provides the first characterization of the neurobehavioural phenotype of 1 year old Cdkl5-null mice and demonstrates that stimulation of the serotonin receptor 7 (5-HT7 R) with the agonist molecule LP-211 (0...
October 13, 2018: Neuropharmacology
Anna Partyka, Magdalena Jastrzębska-Więsek, Lucyna Antkiewicz-Michaluk, Jerzy Michaluk, Agnieszka Wąsik, Vittorio Canale, Paweł Zajdel, Marcin Kołaczkowski, Anna Wesołowska
The aim of the present study was to investigate and compare the ability of three novel 5-HT6 and/or 5-HT7 receptor antagonists as follows: PZ-668-a preferential 5-HT6 antagonist; PZ-1433-a preferential 5-HT7 antagonist; and ADN-1184-a monoaminergic ligand with potent 5HT6/7 antagonist properties, to augment the effect of antidepressant drugs with different mechanisms of action (escitalopram, reboxetine, and bupropion) in the forced swim test in rats. In neurochemical ex vivo experiments, the influence of the tested compounds on levels of monoamines and their metabolites were determined in the rat frontal cortex, in addition to behavioral experiments...
October 9, 2018: Behavioural Brain Research
Arvind Kumar, Harpreet Singh, Amrita Mishra, Arun K Mishra
OBJECTIVE: Aripiprazole,a synthetic compound, obtained by chemical modification of the structure of quinolinone is considered as an atypical antipsychotic drug. The present review is an attempt to summarize the updated information related to reported chemistry and pharmacology of Aripiprazole. DEVELOPMENT: Aripiprazole, under development by Otsuka Pharmaceutical, was approved by the U.S. Food and Drug Administration (USFDA) in the end months of 2002 to with an aim to treat patients with schizophrenia...
October 8, 2018: Current Drug Discovery Technologies
Hyung Gon Lee, Ji A Song, Dong Soo Han, Kyeong Wan Woo, Myung Ha Yoon
This study examined the effects of intrathecal areca nut on spinal nerve-ligated and chemotherapy-induced neuropathic pain (NP), and investigated the relevance of spinal 5-hydroxytryptamine (5-HT) and α2-adrenergic receptors to those effects. For drug administration, intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats. NP was induced either by spinal nerve ligation (left spinal nerves L5 and L6) or by chemotherapeutic injection (intraperitoneal cisplatin, 2 mg/kg/day, once daily for 4 days)...
2018: Pharmacology
Anna Rita Zuena, Daniela Maftei, Giovanni Sebastiano Alemà, Francesca Dal Moro, Roberta Lattanzi, Paola Casolini, Ferdinando Nicoletti
Vortioxetine is a multimodal antidepressant that potently antagonizes 5-HT3 serotonin receptors, inhibits the high-affinity serotonin transporter, activates 5-HT1A and 5-HT1B receptors, and antagonizes 5-HT1D and 5-HT7 receptors. 5-HT3 receptors largely mediate the hyperalgesic activity of serotonin that occurs in response to nerve injury. Activation of 5-HT3 receptors contributes to explain why selective serotonin reuptake inhibitors, such as fluoxetine, are not indicated in the treatment of neuropathic pain...
January 2018: Molecular Pain
Joanna Sowa, Magdalena Kusek, Marcin Siwiec, Joanna Ewa Sowa, Bartosz Bobula, Krzysztof Tokarski, Grzegorz Hess
RATIONALE: Chronic stress and corticosterone have been shown to affect serotonin (5-HT) neurotransmission; however, the influence of stress on the activity of the dorsal raphe nucleus (DRN), the main source of 5-HT in the forebrain, is not well understood. In particular, it is unknown if and how stress modifies DRN 5-HT7 receptors, which are involved in the modulation of the firing of local inhibitory interneurons responsible for regulating the activity of DRN projection cells. OBJECTIVES: Our study aimed to investigate the effect of repeated corticosterone injections on the modulation of the inhibitory transmission within the DRN by 5-HT7 receptors and whether it could be reversed by treatment with a 5-HT7 receptor antagonist...
December 2018: Psychopharmacology
Ahmad Arbabi Jahan, Abolfazl Rad, Mustafa Ghanbarabadi, Bahareh Amin, Mohammad Mohammad-Zadeh
AIM: Curcumin, derived from turmeric, has been demonstrated to be effective in controlling seizures, although the exact mechanism is yet unknown. In this study, the role of serotonin and its receptors in the anticonvulsant effect of curcumin was evaluated in mice. MAIN METHODS: Total 110 mice were randomly divided into 11 groups (n = 10). In the first to the fourth groups, the role of curcumin (150 mg/kg, i.p) and serotonin (PCPA (100 mg/kg); was used to deplete the brain serotonin levels) was investigated...
October 15, 2018: Life Sciences
T E Schwasinger-Schmidt, M Macaluso
This chapter addresses the following FDA-approved medications for the treatment of major depressive disorder available for use in the United States including bupropion, mirtazapine, trazodone, vortioxetine, and vilazodone. These medications do not belong to one of the previously featured classes of antidepressants discussed in the preceding chapters. Each medication featured in this chapter has a unique structure and properties that target diverse receptors in the central nervous system. These diverse targets are distinct from other classes of medications used to treat major depressive disorder...
September 8, 2018: Handbook of Experimental Pharmacology
Rafał Kurczab, Vittorio Canale, Grzegorz Satała, Paweł Zajdel, Andrzej J Bojarski
A computational approach combining a structure-activity relationship library of halogenated and the corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was used to search for amino acids frequently targeted by halogen bonding (hot spots) in a 5-HT7 R as a case study. The procedure identified two sets of hot spots, extracellular (D2.65, T2.64, and E7.35) and transmembrane (C3.36, T5.39, and S5.42), which were further verified by a synthesized library of halogenated arylsulfonamide derivatives of (aryloxy)ethylpiperidines...
September 21, 2018: Journal of Medicinal Chemistry
Krzysztof Miazga, Hanna Fabczak, Ewa Joachimiak, Małgorzata Zawadzka, Łucja Krzemień-Ojak, Marek Bekisz, Anna Bejrowska, Larry M Jordan, Urszula Sławińska
Serotonin (5-hydroxytryptamine; 5-HT) plays an important role in control of locomotion, partly through direct effects on motoneurons. Spinal cord complete transection (SCI) results in changes in 5-HT receptors on motoneurons that influence functional recovery. Activation of 5-HT2A and 5-HT7 receptors improves locomotor hindlimb movements in paraplegic rats. Here, we analyzed the mRNA of 5-HT2A and 5-HT7 receptors (encoded by Htr2a and Htr7 genes, resp.) in motoneurons innervating tibialis anterior (TA) and gastrocnemius lateralis (GM) hindlimb muscles and the tail extensor caudae medialis (ECM) muscle in intact as well as spinal rats...
2018: Neural Plasticity
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