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5HT2C Serotonin Receptor 2C

María Teresa Rivera-García, Carolina López-Rubalcava, Silvia L Cruz
RATIONALE: Toluene is a misused inhalant with hallucinogenic properties and complex effects. Toluene blocks N-methyl-D-aspartate (NMDA) receptors, releases dopamine (DA), and modifies several neurotransmitter levels; nonetheless, the mechanism by which it produces hallucinations is not well characterized. OBJECTIVES: This study aims (a) to study toluene's effects on the 5-HT2A-mediated head-twitch response (HTR), dopamine (DA), and serotonin (5-HT) tissue levels in discrete brain regions; (b) to compare the actions of toluene, ketamine, and 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) on HTR; and (c) to study the pharmacological blockade of toluene's and ketamine's effects by selective drugs...
October 2015: Psychopharmacology
L Samalin, M Ben Gharbia, M Garnier, P-M Llorca
Lurasidone is a new second-generation antipsychotic approved in October 2010 by the Food and Drug Administration and in March 2014 by the European Medicines Agency for the treatment of schizophrenia. Like other second-generation antipsychotics, lurasidone is an antagonist of D2 dopamine and 5HT2A serotonin receptors, but differs from the other second-generation antipsychotics in its action profile for certain receptors. Lurasidone is the second-generation antipsychotic with the greatest affinity for 5HT7 receptors and has a low affinity for α1 and α2C-adrenergic and 5HT2C serotonin receptors, and no affinity for histaminergic H1 or muscarinic M1 receptors...
December 2014: L'Encéphale
James M Kasper, Raymond G Booth, Joanna Peris
The serotonin 5-HT2C receptor has shown promise in vivo as a pharmacotherapeutic target for alcoholism. For example, recently, a novel 4-phenyl-2-N,N-dimethylaminotetralin (PAT) drug candidate, that demonstrates 5-HT2C receptor agonist activity together with 5-HT2A/2B receptor inverse agonist activity, was shown to reduce operant responding for ethanol after peripheral administration to rats. Previous studies have shown that the 5-HT2C receptor is found throughout the mesoaccumbens pathway and that 5-HT2C receptor agonism causes activation of ventral tegmental area (VTA) GABA neurons...
February 2015: Synapse
M Pardini, C Cordano, F Benassi, C Mattei, D Sassos, S Guida, C Serrati, A Primavera, M Amore, L Cocito, L Emberti Gialloreti
Chronic Fatigue Syndrome (CFS) represents a disabling condition characterized by persistent mental and physical fatigue, bodily discomfort and cognitive difficulties. To date the neural bases of CFS are poorly understood; however, mono-aminergic abnormalities, sleep-wake cycle changes and prefrontal dysfunctions are all thought to play a role in the development and maintenance of this condition. Here we explored in a group of 62 CFS subjects the impact on fatigue levels of agomelatine, an antidepressant with agonist activity at melatonin receptors (MT1 and MT2) and antagonist activity at serotoninergic 2C receptors (5HT2C)...
June 2014: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Cheuk Ka Tong, Jiadong Chen, Arantxa Cebrián-Silla, Zaman Mirzadeh, Kirsten Obernier, Cristina D Guinto, Laurence H Tecott, Jose Manuel García-Verdugo, Arnold Kriegstein, Arturo Alvarez-Buylla
The ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (NSCs) in the walls of the lateral ventricles of the adult brain. How the adult brain's neural activity influences the behavior of adult NSCs remains largely unknown. We show that serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on most of the ventricular walls. Electron microscopy revealed intimate contacts between 5HT axons and NSCs (B1) or ependymal cells (E1) and these cells were labeled by a transsynaptic viral tracer injected into the raphe...
April 3, 2014: Cell Stem Cell
Ramesh Neelamegam, Tim Hellenbrand, Frederick A Schroeder, Changning Wang, Jacob M Hooker
The serotonin subtype 2C (5HT2C) receptor is an emerging and promising drug target to treat several disorders of the human central nervous system. In this current report, two potent and selective 5HT2C full agonists, WAY-163909 (2) and vabicaserin (3), were radiolabeled with carbon-11 via Pictet-Spengler cyclization with [(11)C]formaldehyde and used in positron emission tomography (PET) imaging. Reaction conditions were optimized to exclude the major source of isotope dilution caused by the previously unknown breakdown of N,N-dimethylformamide (DMF) to formaldehyde at high temperature under mildly acid conditions...
February 27, 2014: Journal of Medicinal Chemistry
Jorge J Pérez Maceira, María J Mancebo, Manuel Aldegunde
It is known that in fish the serotonergic system is part of the neural network that controls feeding and that a pharmacologically induced increase in the brain 5-HT inhibits food intake. However, nothing is known about the 5-HT receptors involved in this inhibitory effect. In this study, we investigated the effects of several 5-HT1 and 5-HT2 receptor agonists on food intake in rainbow trout. In the first experiment, fish were injected i.p. or i.c.v. with two 5-HT1B receptor agonists, anpirtoline (2mg/kg, i...
April 2014: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
A Akubuiro, M Bridget Zimmerman, L L Boles Ponto, S A Walsh, J Sunderland, L McCormick, M Singh
ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on RNA) show characteristics of overeating and experience adult onset obesity. Behavioral patterns and brain changes related to a possible addictive overeating in these transgenic mice were explored as transgenic mice display chronic hyperphagia. ADAR2 transgenic mice were assessed in their food preference and motivation to overeat in a competing reward environment with ad lib access to a running wheel and food. Metabolic activity of brain and peripheral tissue were assessed with [(18) F] fluorodeoxyglucose positron emission tomography (FDG-PET) and RNA expression of feeding related genes, ADAR2, dopamine and opiate receptors from the hypothalamus and striatum were examined...
April 2013: Genes, Brain, and Behavior
Dániel J Tóth, József T Tóth, Gergö Gulyás, András Balla, Tamas Balla, László Hunyady, Péter Várnai
Receptor endocytosis plays an important role in regulating the responsiveness of cells to specific ligands. Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)] has been shown to be crucial for endocytosis of some cell surface receptors, such as EGF and transferrin receptors, but its role in G-protein-coupled receptor internalization has not been investigated. By using luciferase-labeled type 1 angiotensin II (AT1R), type 2C serotonin (5HT2CR) or β(2) adrenergic (β2AR) receptors and fluorescently tagged proteins (β-arrestin-2, plasma-membrane-targeted Venus, Rab5) we were able to follow the sequence of molecular interactions along the endocytic route of the receptors in HEK293 cells using the highly sensitive method of bioluminescence resonance energy transfer and confocal microscopy...
May 1, 2012: Journal of Cell Science
M M Sidor, A Amath, G MacQueen, J A Foster
An immunogenic challenge during early postnatal development leads to long-term changes in behavioural and physiological measures reflecting enhanced emotionality and anxiety. Altered CNS serotonin (5-HT) signalling during the third postnatal week is thought to modify the developing neurocircuitry governing anxiety-like behaviour. Changes in 5-HT signalling during this time window may underlie increased emotionality reported in early immune challenge rodents. Here we examine both the spatial and temporal profile of 5-HT related gene expression, including 5HT1A, 2A, 2C receptors, the 5-HT transporter (5HTT), and tryptophan hydroxylase 2 (TPH2) during early development (postnatal day [P]14, P17, P21, P28) in mice challenged with lipopolysaccharide (LPS) during the first postnatal week...
December 15, 2010: Neuroscience
Kevin K-C Liu, Peter Cornelius, Terrell A Patterson, Yuan Zeng, Stephanie Santucci, Elizabeth Tomlinson, Colleen Gibbons, Tristan S Maurer, Ravi Marala, Janice Brown, Jimmy X Kong, Eunsun Lee, Wendy Werner, Zane Wenzel, Chandra Vage
Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose-responsive in vivo efficacy in our pre-clinical food intake model.
January 1, 2010: Bioorganic & Medicinal Chemistry Letters
Sofia I I Kring, Thomas Werge, Claus Holst, Søren Toubro, Arne Astrup, Torben Hansen, Oluf Pedersen, Thorkild I A Sørensen
BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs) of these genes with obesity and metabolic traits. METHODOLOGY/PRINCIPAL FINDINGS: In a population of 166 200 young men examined at the draft boards, obese men (n = 726, BMI> or =31...
2009: PloS One
J A Henderson, C L Bethea
To further understand the role of ovarian hormones in the function of the serotonin neural system, we investigated the effects of estradiol (E), progesterone (P), and raloxifene on 5HT 1A and 2C receptor protein expression in the dorsal raphe region using Western blot analysis. Adult rhesus macaques (Macaca mulatta) were ovariectomized (Ovx) and implanted with Silastic capsules containing E or P. In the first paradigm, animals that had been Ovx for 6-16 months were treated for 1 month with E (El) or E + P (EP1) and compared to animals that were untreated and Ovx for 5 months (n = 4 per group)...
June 2008: Endocrine
Tim D Werry, Richard Loiacono, Patrick M Sexton, Arthur Christopoulos
The process of RNA editing involves the modification of mRNA at specific sites by adenosine deaminases that act on RNA (ADAR) enzymes. By catalyzing the conversion of adenosine to inosine, these enzymes alter the way in which the mRNA is translated, and consequently alter the primary structure of the resultant proteins. The serotonin (5HT) 2C receptor (5HT2CR) is currently the only known member of the superfamily of seven transmembrane domain receptors (7TMRs) to undergo this modification, and provides a fascinating case study in the effects of such changes...
July 2008: Pharmacology & Therapeutics
Aya Nakae, Kunihiro Nakai, Tatsuya Tanaka, Saotoshi Hagihira, Masahiko Shibata, Koichi Ueda, Takashi Masimo
We examined whether infraorbital nerve injury affected the RNA editing efficiency of the serotonin (5HT) 2C receptor in the cervical spinal cord, in association with increased pain thresholds, and whether a 5HT reuptake inhibitor (fluvoxamine; Depromel, Meiji Seika, Tokyo, Japan) altered this editing. Accordingly, we injured rats with an infraorbital nerve loose ligation and examined the pain thresholds, mRNA and mRNA editing of the 5HT2C receptor. We evaluated changes in mRNA editing and 5HT2C mRNA expression using cloning along with sequence analysis and quantitative reverse transcription-polymerase chain reaction to compare samples taken at post-injury day 28 from spinal cord sites, including the trigeminal nucleus caudalis, in naive, sham and injured rats (groups of each type had also received fluvoxamine)...
May 2008: European Journal of Neuroscience
Aya Nakae, Kunihiro Nakai, Tatsuya Tanaka, Masaki Takashina, Satoshi Hagihira, Masahiko Shibata, Koichi Ueda, Takashi Mashimo
We investigated the effects on 5HT(serotonin) 2C receptor RNA editing efficiency of contusive SCI (spinal cord injury). Using cloning followed by sequence analysis on spinal cord samples taken, we compared mRNA editing. Our results might be evidence of a functional adaptation mechanism in which increased expression of 5HT2C mRNA isoforms that encode receptors more sensitive to serotonin works to activate brainstem-spinal descending 5HT systems to, in effect, suppress transmission of nociceptive signals from primary afferent neurons to the spinal dorsal horn...
February 2008: Neuroscience Research
Sudhir C Sharma, Chamila N Rupasinghe, Rachel B Parisien, Mark R Spaller
PDZ10 is the 10th of 13 PDZ domains found within MUPP1, a cytoplasmic scaffolding protein first identified as an endogenous binding partner of serotonin receptor type 2c (5HT2c). This association, as with those of several other interacting proteins that have subsequently been identified, is mediated through the C-terminal tail of the PDZ domain partner. Using isothermal titration calorimetry (ITC), we measured the thermodynamic binding parameters [changes in Gibbs free energy (DeltaG), enthalpy (DeltaH) and entropy (TDeltaS)] of the isolated PDZ10 domain for variable-length N-acetylated peptides from the 5HT2c serotonin receptor C-terminal sequence, as well as for octapeptides of eight other putative partner proteins of PDZ10 (5HT2a, hc-kit, hTapp1, mTapp2, TARP, NG2, claudin-1, and HPV-18 E6)...
November 6, 2007: Biochemistry
Vanessa Nunes-de-Souza, Ricardo Luiz Nunes-de-Souza, Robert John Rodgers, Azair Canto-de-Souza
It is widely acknowledged that the indoleamine neurotransmitter serotonin (5-HT) plays a dual role in the regulation of anxiety, a role that in part depends upon neuroanatomical locus of action. Thus, whereas stimulation of 5-HT 1A or 5-HT2 receptors in the limbic forebrain (amygdala, hippocampus) enhances anxiety-like responding in rodents, activation of corresponding receptor populations in the midbrain periaqueductal grey (PAG) more often than not reduce anxiety-like behaviour. The present study specifically concerns the anxiety-modulating influence of 5-HT2 receptors within the mouse PAG...
February 11, 2008: Behavioural Brain Research
Maria-Luisa Centeno, Rachel L Sanchez, Judy L Cameron, Cynthia L Bethea
Like women, female cynomolgus monkeys show differential sensitivity to stress-induced reproductive dysfunction. A combined social and metabolic stress (mild diet+moderate exercise+relocation) will rapidly induce anovulation in a third of female cynomolgus monkeys (stress-sensitive; SS); a third will ovulate once and then become anovulatory (medium stress-resilient; MSR) and a third are highly stress-resilient (HSR) and exhibit normal menstrual cycles through two stressed menstrual cycles. In a non-stressed menstrual cycle, SS animals have lower levels of estrogen and progesterone, lower activity of the serotonin system and lower expression of genes related to the serotonin system in the dorsal raphe nucleus...
April 20, 2007: Brain Research
Biao Wang, Farid F Chehab
The binding of leptin to hypothalamic neurons elicits inhibition of orexigenic NPY/AgRP neurons and stimulation of anorexigenic POMC/CART neurons. Projections of serotonergic neurons onto POMC neurons suggest that leptin and serotonin converge onto POMC neurons to regulate body weight. We probed the interaction of these pathways by generating transgenic mice overexpressing leptin (LepTg) without 5HT2c receptors. On a chow diet, the lean phenotype of LepTg mice was unaffected by the absence of 5HT2c receptors, whereas on a high fat diet, LepTg/5HT2c receptors knockout mice showed an exacerbation of diet-induced obesity...
December 15, 2006: Biochemical and Biophysical Research Communications
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