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Kanako Terakado Kimura, Hidetsugu Asada, Asuka Inoue, Francois Marie Ngako Kadji, Dohyun Im, Chihiro Mori, Takatoshi Arakawa, Kunio Hirata, Yayoi Nomura, Norimichi Nomura, Junken Aoki, So Iwata, Tatsuro Shimamura
Many drugs target the serotonin 2A receptor (5-HT2A R), including second-generation antipsychotics that also target the dopamine D2 receptor (D2 R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT2A R in complex with the second-generation antipsychotics risperidone and zotepine. These antipsychotics effectively stabilize the inactive conformation by forming direct contacts with the residues at the bottom of the ligand-binding pocket, the movements of which are important for receptor activation...
February 2019: Nature Structural & Molecular Biology
Sean C Godar, Laura J Mosher, Simona Scheggi, Paola Devoto, Kelly M Moench, Hunter J Strathman, Cori M Jones, Roberto Frau, Miriam Melis, Carla Gambarana, Brent Wilkinson, M Graziella DeMontis, Stephen C Fowler, Marcelo P Coba, Cara L Wellman, Jean C Shih, Marco Bortolato
The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes...
February 1, 2019: Neuropharmacology
Simin Afshar, Siamak Shahidi, Ali Haeri Rohani, Sara Soleimani Asl, Alireza Komaki
Alzheimer's disease (AD) is a neurodegenerative disorder and neuropathologically characterized by the aggregation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, enhanced oxidative stress and neurodegeneration. Involvement of serotonergic systems in AD has been supposed and it is suggested that serotonin receptors modulation may provide a novel therapeutic target for AD. This study aimed at investigating the protective effect of NAD-299 (the selective 5-HT1A receptor antagonist) and TCB-2 (the potent5-HT2A receptor agonist) on the hippocampal oxidative stress biomarkers and the number of intact neurons in streptozotocin (STZ)-induced Alzheimer's disease in rats...
January 23, 2019: Journal of Chemical Neuroanatomy
Amanda E Price, Dennis J Sholler, Sonja J Stutz, Noelle C Anastasio, Kathryn A Cunningham
The 5-HT2A receptor (5-HT2A R) and 5-HT2C R are localized to the same neurons within the medial prefrontal cortex (mPFC), which regulates executive function, decision-making, and reward-guided learning and memory processes. The 5-HT2A R and 5-HT2C R co-immunoprecipitate in the mPFC of male, Sprague-Dawley rats, while in vitro studies demonstrate the presence of a physical interaction between the 5-HT2A R and 5-HT2C R. The purpose of this study was to identify mPFC subregions in which the 5-HT2A R and 5-HT2C R physically interact ex vivo in the male Sprague-Dawley rat...
January 15, 2019: ACS Chemical Neuroscience
(no author information available yet)
No abstract text is available yet for this article.
February 2019: Molecular Pharmacology
Mona El Refaey, Hassan Musa, Nathaniel P Murphy, Ellen Lubbers, Michel Skaf, Mei Han, Omer Cavus, Sara Nichole Koenig, Michael Jameson Wallace, Daniel Gratz, Elisa Bradley, Katherina M Alsina, Xander Ht Wehrens, Thomas J Hund, Peter J Mohler
RATIONALE: Voltage-gated Na+ channel ( INa ) function is critical for normal cardiac excitability. However, the Na+ channel "late" component ( INa,L ) is directly associated with potentially fatal forms of congenital and acquired human arrhythmia. Ca2+ /calmodulin-dependent kinase II (CaMKII) enhances INa,L in response to increased adrenergic tone. However, the pathways that negatively regulate the CaMKII/Nav1.5 axis are unknown and essential for the design of new therapies to regulate the pathogenic INa,L ...
January 3, 2019: Circulation Research
Radhika Sudhir Joshi, Shishu Pal Singh, Mitradas M Panicker
Clozapine is an antipsychotic known for its superior efficacy in treating drug-resistant Schizophrenia. However, Clozapine induces various side effects such as hyperglycemia, agranulocytosis, weight gain etc. The mechanisms of these Clozapine-induced side effects have remained largely elusive though an important role is ascribed to 5-HT2A (Serotonin receptor subtype-2A). In this pilot study, we report for the first time that the 5-HT2A 'global' knockout mice (Htr2a-/- ) are resistant to the Clozapine-induced hyperglycemia...
December 18, 2018: Journal of Pharmacological Sciences
Liangliang Zhou, Minxuan Cai, Yingying Ren, Huali Wu, Meng Liu, Haijuan Chen, Jing Shang
BACKGROUND: 5-HT1A receptor was participated in fluoxetine induced melanogenesis in melanocytes and in normal C57BL/6 mice, but we know little about whether other 5-HT receptors are involved in regulation of fluoxetine promotes pigmentation. OBJECTIVE: To investigate the role of 5-HT receptors in regulation of fluoxetine ameliorates chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) induce hypopigmentation in C57BL/6 mice. METHODS: CUMS and CRS were used to induce depigmentation in mice and evaluate the effect of fluoxetine...
December 2018: Journal of Dermatological Science
Federico Zamberlan, Camila Sanz, Rocío Martínez Vivot, Carla Pallavicini, Fire Erowid, Earth Erowid, Enzo Tagliazucchi
Classic psychedelics are substances of paramount cultural and neuroscientific importance. A distinctive feature of psychedelic drugs is the wide range of potential subjective effects they can elicit, known to be deeply influenced by the internal state of the user ("set") and the surroundings ("setting"). The observation of cross-tolerance and a series of empirical studies in humans and animal models support agonism at the serotonin (5-HT)2A receptor as a common mechanism for the action of psychedelics...
2018: Frontiers in Integrative Neuroscience
Philippe Huot
No abstract text is available yet for this article.
December 2018: Neurodegenerative Disease Management
Cynthia Kwan, Imane Frouni, Dominique Bédard, Stephen G Nuara, Jim C Gourdon, Adjia Hamadjida, Philippe Huot
Virtually every patient affected by Parkinson's disease (PD) eventually requires treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), which leads to complications such as dyskinesia and psychosis. Whereas blockade of serotonin 2A (5-HT2A ) receptors appears to be an effective way to reduce both dyskinesia and psychosis, whether it has the potential to eliminate the two phenomena remains to be determined. In a previous study, we showed that highly selective 5-HT2A receptor blockade with EMD-281,014, at plasma levels comparable to those achieved in the clinic, reduced dyskinesia and psychosis-like behaviours (PLBs), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset...
November 15, 2018: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
Nathalie Lombaert, Maroussia Hennes, Sara Gilissen, Giel Schevenels, Laetitia Aerts, Ria Vanlaer, Lieve Geenen, Ann Van Eeckhaut, Ilse Smolders, Julie Nys, Lutgarde Arckens
Visual cortical areas show enhanced tactile responses in blind individuals, resulting in improved behavioral performance. Induction of unilateral vision loss in adult mice, by monocular enucleation (ME), is a validated model for such cross-modal brain plasticity. A delayed whisker-driven take-over of the medial monocular zone of the visual cortex is preceded by so-called unimodal plasticity, involving the potentiation of the spared-eye inputs in the binocular cortical territory. Full reactivation of the sensory-deprived contralateral visual cortex is accomplished by 7 weeks post-injury...
November 6, 2018: Molecular Brain
Dennis J Sholler, Sonja J Stutz, Robert G Fox, Edward L Boone, Qin Wang, Kenner C Rice, F Gerard Moeller, Noelle C Anastasio, Kathryn A Cunningham
Impulsivity and the responsivity to cocaine-linked cues ("cue reactivity") promote relapse in cocaine use disorder (CUD). A time-dependent escalation of cue reactivity ("incubation") occurs during extended forced abstinence (FA) from cocaine self-administration. The investigational serotonin (5-HT) 5-HT2A receptor (5-HT2A R) antagonist/inverse agonist M100907 suppresses impulsive action (inability to withhold premature responses) and cocaine-seeking behavior. The recent approval of the 5-HT2A R antagonist/inverse agonist pimavanserin (NUPLAZID™) provides the opportunity to assess an FDA-approved medication in preclinical analyses of relapse vulnerability...
October 29, 2018: Journal of Pharmacology and Experimental Therapeutics
E A Kulikova, N V Khotskin, N B Illarionova, I E Sorokin, E Y Bazhenova, E M Kondaurova, K P Volcho, T M Khomenko, N F Salakhutdinov, E Ponimaskin, V S Naumenko, A V Kulikov
The serotoninergic 5-HT2A receptor is involved in the mechanism of depression and antidepressant drugs action. Earlier we showed that striatal-enriched protein tyrosine phosphatase (STEP) inhibitor - 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153) affects both the brain serotoninergic system and the brain-derived neurotropic factor that are known to be involved in the psychopathology of depression. In the present study we investigated the effects of chronic TC-2153 administration on behavior in the standard battery of tests as well as the effects of acute and chronic TC-2153 treatment on the brain 5-HT2A receptors in mice...
December 1, 2018: Neuroscience
Yuka Nakamura, Yoshihisa Kitamura, Yusuke Sumiyoshi, Nanami Naito, Shiho Kan, Soichiro Ushio, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo
We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT)2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light-dark test. In addition, we examined the rats' 5-HT2A receptor-mediated behavioral responses...
November 2018: Journal of Pharmacological Sciences
Cristina Alba-Delgado, Sarah Mountadem, Noémie Mermet-Joret, Lénaïc Monconduit, Radhouane Dallel, Alain Artola, Myriam Antri
Mechanical allodynia, a widespread pain symptom which still lacks effective therapy, is associated with the activation of a dorsally-directed polysynaptic circuit within spinal (SDH) or medullary dorsal horn (MDH), whereby tactile inputs into deep SDH/MDH can gain access to superficial SDH/MDH, eliciting pain. Inner lamina II (IIi ) interneurons expressing the γ isoform of protein kinase C (PKCγ+ ) are key elements for allodynia circuits but how they operate is still unclear. Combining behavioral, ex vivo electrophysiological and morphological approaches in an adult rat model of facial inflammatory pain (Complete Freund's Adjuvant, CFA), we show that the mechanical allodynia observed 1h after CFA injection is associated with i) sensitization (using ERK1/2 phosphorylation as a marker) and ii) reduced dendritic arborizations and enhanced spine density-in exclusively PKCγ+ interneurons, but iii) depolarized resting membrane potential (RMP) in all lamina IIi PKCγ+ /PKCγ- interneurons...
October 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Simona Denise Frederiksen, Karin Warfvinge, Lena Ohlsson, Lars Edvinsson
Neurotransmitter and headache target localization in the trigeminal ganglia (TG) might increase the understanding of sites of action, and mechanisms related to headache therapy. The overall aim of the study was to investigate the presence of migraine targets in the TG with particular emphasis on pituitary adenylate cyclase-activating peptide (PACAP) and calcitonin gene-related peptide (CGRP), known to be involved in cranial pain processing, and selected headache targets. Rat- and human TG were processed for immunohistochemistry...
October 15, 2018: Neuroscience
Anna Herman, Mostafa El Mansari, Nika Adham, Béla Kiss, Bence Farkas, Pierre Blier
Cariprazine, an orally active and potent dopamine D3 -preferring D3 /D2 receptor partial agonist, is approved to treat adults with schizophrenia (in the United States and Europe) and manic or mixed episodes associated with bipolar I disorder (in the United States). Cariprazine also displays partial agonism at serotonin [5-hydroxytryptamine (5-HT)] 5-HT1A receptors and antagonism at 5-HT2A and 5-HT2B receptors in vitro. The study objective was to determine whether cariprazine leads to functional alterations of monoamine systems in vivo via electrophysiological recordings from anesthetized rats...
December 2018: Molecular Pharmacology
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
Imane Frouni, Cynthia Kwan, Dominique Bédard, Sébastien Belliveau, Élodie Bourgeois-Cayer, Fleur Gaudette, Francis Beaudry, Adjia Hamadjida, Philippe Huot
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective therapy for motor symptoms of Parkinson's disease (PD); however, with repeated administration, as many as 94% of PD patients develop complications such as L-DOPA-induced dyskinesia. We previously demonstrated that EMD-281,014, a highly selective serotonin 2A (5-HT2A ) receptor antagonist, reduces the severity of dyskinesia in the parkinsonian marmoset, without interfering with L-DOPA anti-parkinsonian benefit. Here, we assessed the effects of EMD-281,014 on L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat...
October 8, 2018: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
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