DOCSLIB.ORG

Differential Regulation of Mecp2 Phosphorylation in the CNS by Dopamine and Serotonin

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Differential Regulation of Mecp2 Phosphorylation in the CNS by Dopamine and Serotonin Neuropsychopharmacology (2012) 37, 321–337 & 2012 American College of Neuropsychopharmacology. All rights reserved 0893-133X/12 www.neuropsychopharmacology.org Differential Regulation of MeCP2 Phosphorylation in the CNS by Dopamine and Serotonin 1 1 2 1,2,3,4 ,1 Ashley N Hutchinson , Jie V Deng , Dipendra K Aryal , William C Wetsel and Anne E West* 1 2 Department of Neurobiology, Duke University Medical Center, Durham, NC, USA; Department of Psychiatry and Behavioral Sciences, Duke 3 University Medical Center, Durham, NC, USA; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, 4 Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional- and cell-type specificity of pMeCP2 induction. The D1-class DA receptor agonist SKF81297 induced pMeCP2 widely; however, coadministration of the D2-class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. Intra-striatal injection of the adenylate cyclase activator forskolin was sufficient to induce pMeCP2 in medium-spiny neurons, suggesting that the combinatorial regulation of cAMP by different classes of DA and 5-HT receptors may contribute to the cell-type specificity of pMeCP2 induction. Consistent with the regulation of pMeCP2 by multiple monoamine neurotransmitters, genetic disruption of any single monoamine transporter in DAT-, SERT-, and NET- knockout mice failed to eliminate AMPH-induced pMeCP2 in the NAc. Together, these studies indicate that combinatorial signaling through DA and 5-HT receptors can regulate the brain region- and cell-type specific pMeCP2 in the CNS. Neuropsychopharmacology (2012) 37, 321–337; doi:10.1038/npp.2011.190; published online 28 September 2011 Keywords: MeCP2; monoamine transporters; signal transduction; dopamine; serotonin; nucleus accumbens INTRODUCTION A substantial body of evidence indicates that psychostim- ulant-induced changes in gene expression contribute to the Psychostimulant-induced activation of monoamine recep- long-lasting effects of these drugs on behavior (Nestler, tors is essential to the mechanism by which these drugs 2008; Kumar et al, 2005). Examination of the molecular induce changes in behavior (Gainetdinov and Caron, 2003; processes underlying these changes in gene expression has Missale et al, 1998; Xu et al, 1997). Cocaine and revealed a significant role for epigenetic mechanisms of amphetamine (AMPH) serve as indirect monoamine transcription, which are processes that mediate changes receptor agonists by inhibiting and/or reversing the in gene expression by regulating chromatin structure function of monoamine transporters. However, despite the (Maze et al, 2010; Renthal et al, 2009). Therefore, chromatin fact that these drugs rapidly increase extracellular levels of regulatory proteins that are targets of modulation by dopamine (DA), serotonin (5-HT), and norepinephrine monoaminergic signaling pathways are strong candidates (NE), repeated exposure is necessary to produce long- to link psychostimulant exposure to persistent changes in lasting alterations in behavior (Hyman et al, 2006). This gene expression and behavior. Recently, we and others have observation suggests that molecular mechanisms down- demonstrated that the methyl-CpG-binding protein-2 stream of monoamine receptor activation are required to (MeCP2) contributes to both neural and behavioral adapta- mediate the observed behavioral adaptations. tions induced by repeated psychostimulant exposure (Deng et al, 2010; Im et al, 2010). We have shown that lentiviral shRNA-mediated knockdown of MeCP2 in the nucleus *Correspondence: Dr AE West, Department of Neurobiology, Duke accumbens (NAc) increases sensitivity to AMPH-induced University Medical Center, Box 3209, Durham, NC 27710, USA, conditioned place-preference (CPP) whereas overexpression Tel: + 1 919 681 1909, Fax: + 919 684 4431, of MeCP2 decreases CPP (Deng et al, 2010). These data E-mail: [email protected] suggest that MeCP2 acts in the NAc to limit the rewarding Received 29 March 2011; revised 29 July 2011; accepted 29 July 2011 properties of psychostimulants. Differential regulation of MeCP2 phosphorylation AN Hutchinson et al 322 Psychostimulants induce rapid and robust phosphoryla- 21–30 days of age, housed in groups of 3–5, and segregated tion of MeCP2 at Ser421 (pMeCP2), a site that is thought to by sex and genotype. All animals were given free access to modulate MeCP2-dependent chromatin regulation (Deng standard laboratory chow and water and were housed in a et al, 2010; Zhou et al, 2006; Chen et al, 2003). MeCP2 humidity- and temperature-controlled room on a 14-h/10-h regulates gene transcription by binding to methylated DNA light/dark cycle (lights on at 0700 hours). All experiments and recruiting enzymes that modify histones (Nan et al, were conducted with an approved protocol from the Duke 1998). Although the specific mechanisms by which Ser421 University Institutional Animal Care and Use Committee in phosphorylation affects MeCP2 function remain poorly accordance with the guidelines from the National Institutes understood, overexpression of a Ser421Ala mutant MeCP2 of Health for the Care and Use of Laboratory Animals. has been shown to inhibit neuronal activity-induced Bdnf expression, suggesting that Ser421 phosphorylation could Immunofluorescent Staining of the Brain Sections contribute to gene derepression (Zhou et al, 2006). Interestingly, systemic administration of AMPH induces a Two hours after vehicle or drug injection, mice were perfused restricted pattern of pMeCP2 induction in select neurons transcardially with 4% paraformaldehyde in 0.1 M PBS. The of the NAc and prelimbic cortex (PLC) (Deng et al, 2010). brains were post-fixed in 4% paraformaldehyde/PBS over- D1-class DA receptor activation is required for AMPH- night, then sunk into 20% (wt/vol) sucrose/PBS overnight. dependent induction of pMeCP2 in the NAc, and admin- Coronal sections (40 mm) were cut on a freezing microtome, istration of a D1-class DA receptor agonist is sufficient to and the brain regions were identified by anatomical land- induce pMeCP2 (Deng et al, 2010). However, AMPH marks. One section from each brain region of interest was induces pMeCP2 selectively in GAD67- and parvalbumin- selected for each mouse, based upon anatomical structures to positive GABAergic interneurons of the NAc whereas it fails represent the closest approximation of identical sections to induce pMeCP2 in medium-spiny neurons (MSNs), between individual mice. To minimize technical variations in despite the fact that these cells express high levels of DA immunostaining across genotypes, sections from different receptors. In addition to its effects on DA neurotransmis- individual mice were first photographed for visual identifica- sion, AMPH also impacts 5-HT and NE neurotransmission. tion. The sections were then pooled and incubated with Thus, we considered the possibility that the selective pattern antibodies in a single chamber, and finally they were of pMeCP2 induced by AMPH might arise as a result of separated after processing for image analysis (see Deng combinatorial signaling through one or more of these et al, 2010). For immunostaining, tissue sections were monoaminergic systems. permeabilized with either 1% (vol/vol) (for the pMeCP2 Here, we use both pharmacological and genetic tech- antibody) or 0.3% (vol/vol) (all other antibodies) Triton X- niques to characterize the differential roles of DA, 5-HT, 100 for 1 h and then sections were blocked with 3% (wt/vol) and NE signaling in the regulation of the regional BSA (for the DARPP-32 antibody) or 16% (vol/vol) goat distribution and cell-type specificity of pMeCP2 induction. serum (all other antibodies) in PBS. Sections were incubated We find that selective inhibition of either the DA with the following primary antibodies overnight at 4 1C: rabbit transporter (DAT) or 5-HT transporter (SERT) but not anti-phospho-Ser421 MeCP2 1:15 000 (Deng et al, 2010), the NE transporter (NET) is sufficient to induce pMeCP2 in mouse anti-GAD67 1:500 (MAB5406; Chemicon/Millipore, the NAc. However, only DAT inhibition induces pMeCP2 in Billerica, MA), rabbit anti-c-Fos 1:15 000 (PC38; Calbiochem, the PLC. We also find that differential activation of specific San Diego, CA), goat anti-DARPP-32 1:50 (sc31519; Santa classes of DA and 5-HT receptors induces pMeCP2 in Cruz Biotechnology, Santa Cruz, CA), and mouse anti-GFAP distinct cell types and brain regions, suggesting that 1:100 (Clone G-A-5; Sigma, St Louis, MO). Whenever possible, combinatorial signaling through these receptors sculpts double immunostaining with primary antibodies raised in the specific pattern
Load more

Recommended publications
  • 4695389.Pdf (3.200Mb)
    Non-classical amine recognition evolved in a large clade of olfactory receptors The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Li, Qian, Yaw Tachie-Baffour, Zhikai Liu, Maude W Baldwin, Andrew C Kruse, and Stephen D Liberles. 2015. “Non-classical amine recognition evolved in a large clade of olfactory receptors.” eLife 4 (1): e10441. doi:10.7554/eLife.10441. http://dx.doi.org/10.7554/ eLife.10441. Published Version doi:10.7554/eLife.10441 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993622 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA RESEARCH ARTICLE Non-classical amine recognition evolved in a large clade of olfactory receptors Qian Li1, Yaw Tachie-Baffour1, Zhikai Liu1, Maude W Baldwin2, Andrew C Kruse3, Stephen D Liberles1* 1Department of Cell Biology, Harvard Medical School, Boston, United States; 2Department of Organismic and Evolutionary Biology, Museum of Comparative Zoology, Harvard University, Cambridge, United States; 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States Abstract Biogenic amines are important signaling molecules, and the structural basis for their recognition by G Protein-Coupled Receptors (GPCRs) is well understood. Amines are also potent odors, with some activating olfactory trace amine-associated receptors (TAARs). Here, we report that teleost TAARs evolved a new way to recognize amines in a non-classical orientation.
    [Show full text]
  • Neurotransmitters-Drugs Andbrain Function.Pdf
    Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Edited by R. A. Webster Department of Pharmacology, University College London, UK JOHN WILEY & SONS, LTD Chichester Á New York Á Weinheim Á Brisbane Á Singapore Á Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright # 2001 by John Wiley & Sons Ltd. Bans Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International ++44) 1243 779777 e-mail +for orders and customer service enquiries): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P0LP,UK, without the permission in writing of the publisher. Other Wiley Editorial Oces John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany John Wiley & Sons Australia, Ltd.
    [Show full text]
  • File Download
    Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord Elizabeth A. Gozal, Emory University Brannan E. O'Neill, Emory University Michael A. Sawchuk, Emory University Hong Zhu, Emory University Mallika Halder, Emory University Chou Ching-Chieh , Emory University Shawn Hochman, Emory University Journal Title: Frontiers in Neural Circuits Volume: Volume 8 Publisher: Frontiers | 2014-11-07, Pages 134-134 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.3389/fncir.2014.00134 Permanent URL: https://pid.emory.edu/ark:/25593/mr95r Final published version: http://dx.doi.org/10.3389/fncir.2014.00134 Copyright information: © 2014 Gozal, O'Neill, Sawchuk, Zhu, Halder, Chou and Hochman. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits distribution of derivative works, making multiple copies, distribution, public display, and publicly performance, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author, copyright and license notices be kept intact. Accessed September 27, 2021 11:18 AM EDT ORIGINAL RESEARCH ARTICLE published: 07 November 2014 NEURAL CIRCUITS doi: 10.3389/fncir.2014.00134 Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord Elizabeth A. Gozal , Brannan E. O’Neill , Michael A. Sawchuk , Hong Zhu , Mallika Halder , Ching-Chieh Chou and Shawn Hochman* Physiology Department, Emory University, Atlanta, GA, USA Edited by: The trace amines (TAs), tryptamine, tyramine, and β-phenylethylamine, are synthesized Brian R.
    [Show full text]
  • Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines
    ORIGINAL RESEARCH published: 28 November 2019 doi: 10.3389/fphar.2019.01423 Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines Karolina E. Kolaczynska 1, Dino Luethi 1,2, Daniel Trachsel 3, Marius C. Hoener 4 and Matthias E. Liechti 1* 1 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland, 2 Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria, 3 ReseaChem GmbH, Burgdorf, Switzerland, 4 Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland Background: 2,4,5-Trimethoxyamphetamine (TMA-2) is a potent psychedelic compound. Structurally related 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and phenethylamine congeners (2C-O derivatives) have been described but their pharmacology Edited by: is mostly undefined. Therefore, we examined receptor binding and activation profiles of M. Foster Olive, these derivatives at monoamine receptors and transporters. Arizona State University, United States Methods: Receptor binding affinities were determined at the serotonergic 5-HT1A, 5-HT2A, Reviewed by: Luc Maroteaux, and 5-HT2C receptors, trace amine-associated receptor 1 (TAAR1), adrenergic α1 and INSERM U839 Institut du Fer à α2 receptors, dopaminergic D2 receptor, and at monoamine transporters, using target- Moulin, France Simon D. Brandt, transfected cells. Additionally, activation of 5-HT2A and 5-HT2B receptors and TAAR1 was Liverpool John Moores University, determined. Furthermore, we assessed monoamine transporter inhibition. United Kingdom Results: Both the phenethylamine and amphetamine derivatives (Ki = 8–1700 nM and *Correspondence: Matthias E. Liechti 61–4400 nM, respectively) bound with moderate to high affinities to the 5-HT2A receptor [email protected] with preference over the 5-HT1A and 5-HT2C receptors (5-HT2A/5-HT1A = 1.4–333 and Specialty section: 5-HT2A/5-HT2C = 2.1–14, respectively).
    [Show full text]
  • Pharmacovigilance in Psychiatry Pharmacovigilance in Psychiatry
    Edoardo Spina Gianluca Trifi rò Editors Pharmacovigilance in Psychiatry Pharmacovigilance in Psychiatry Edoardo Spina • Gianluca Trifi rò Editors Pharmacovigilance in Psychiatry Editors Edoardo Spina Gianluca Trifi rò Department of Clinical and Experimental Department of Clinical and Experimental Medicine Medicine University of Messina University of Messina Messina Messina Italy Italy ISBN 978-3-319-24739-7 ISBN 978-3-319-24741-0 (eBook) DOI 10.1007/978-3-319-24741-0 Library of Congress Control Number: 2015957257 Springer Cham Heidelberg New York Dordrecht London © Springer International Publishing Switzerland 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.
    [Show full text]
  • Diverse Antidepressants Increase CDP-Diacylglycerol Production and Phosphatidylinositide Resynthesis in Depression-Relevant Regions of the Rat Brain
    City University of New York (CUNY) CUNY Academic Works Publications and Research City College of New York 2008 Diverse Antidepressants Increase CDP-Diacylglycerol Production and Phosphatidylinositide Resynthesis in Depression-Relevant Regions of the Rat Brain Kimberly R. Tyeryar Laboratory of Integrative Neuropharmacology, University of Maryland School of Pharmacy Ashiwel S. Undieh CUNY City College Habiba OU Vongtau University of Maryland How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/cc_pubs/209 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/5633846 Diverse antidepressants increase CDP- diacylglycerol production and phosphatidylinositide resynthesis in depression- relevant regions of the rat brain ARTICLE in BMC NEUROSCIENCE · FEBRUARY 2008 Impact Factor: 2.67 · DOI: 10.1186/1471-2202-9-12 · Source: PubMed CITATIONS READS 11 26 3 AUTHORS: Kimberly Tyeryar Habiba Vongtau University of North Carolina at Chapel Hill University of Pittsburgh 10 PUBLICATIONS 305 CITATIONS 15 PUBLICATIONS 272 CITATIONS SEE PROFILE SEE PROFILE Ashiwel S Undieh Thomas Jefferson University 42 PUBLICATIONS 1,651 CITATIONS SEE PROFILE Available from: Ashiwel S Undieh Retrieved on: 04 December 2015 BMC Neuroscience BioMed Central Research article Open Access
    [Show full text]
  • Major Depressive Disorder File
    MAJOR DEPRESSIVE DISORDER MAJOR DEPRESSIVE DISORDER • Major depressive disorder (MDD) is a debilitating disease that is characterized by at least one discrete depressive episode lasting at least 2 weeks and involving clear-cut changes in mood, interests and pleasure, changes in cognition and vegetative symptoms • MDD is a heterogeneous disorder, and is often associated with other psychiatric conditions, including anxiety, eating disorders and drug addiction MAJOR DEPRESSIVE DISORDER • The symptoms of depression include emotional and biological components. Emotional symptoms include • Emotional symptoms include • Low mood, excessive rumination of negative thought, misery, apathy and pessimism • Low self-confidence: • feelings of guilt • inadequacy • ugliness • Indecisiveness, loss of motivation • Anhedonia, loss of reward • Biological symptoms include • Retardation of thought and action • Loss of libido • Sleep disturbance and loss of appetite MAJOR DEPRESSIVE DISORDER • Mechanisms/pathophysiology • Genetics • MDD is highly polygenic and involves many genes with small effects • Gene-environment interactions • The lack of consistent and replicated findings in genetic studies for MDD can at least partly be explained by the fact that relevant genetic variants confer an increased risk only in the presence of exposure to stressors and other adverse environmental circumstances • Environmental factors • There is a clear evidence of a dose– response relationship between the number and severity of adverse life events and the risk, severity and chronicity
    [Show full text]
  • Corticosteroids Regulate Brain Hippocampal SHT,, Receptor Mrna Expression
    The Journal of Neuroscience, March 1993, 13(3): 914-923 Corticosteroids Regulate Brain Hippocampal SHT,, Receptor mRNA Expression D. T. Chalmers, S. P. Kwak, A. Mansour, H. Akil, and S. J. Watson Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 48109 Using in situ hybridization techniques, the expression of ology of depressive illness and other affective disorders. In ad- 5-HT,, receptor mRNA was measured within the hippocam- dition to neuroendocrine function, serotonergic transmission is pal formation after bilateral adrenalectomy (ADX). After 24 implicated in normal and abnormal mental states (Eison, 1990) hr ADX, 5HT,, receptor mRNA expression was significantly and selective serotonergic compounds are clinically effective increased in all hippocampal subfields in ADX animals rel- antidepressants and anxiolytics (Cohn and Wilcox, 1985; Traber ative to sham-operated controls (SHAM). The magnitude of and Glaser, 1987). Thus, it is likely that the functional inter- the increase was most pronounced within CA2 (127%) and actions between the HPA system and the central serotonergic CA3/4 (94%)subfields of dorsal hippocampus, intermediate system may be significant, providing a biochemical basis for in the dentate gyrus (73%), and least within CA1 (60%). hormonally induced alterations in CNS circuits. Administration of exogenous cotticosterone (CORT) at the Corticosteroids have been shown to alter several elements of time of ADX maintained the level of 5-HT,, receptor mRNA serotonergic neurotransmission. Removal of circulating corti- expression within the range of SHAM animals. In vitro re- costeroids by adrenalectomy (ADX) results in anatomically spe- ceptor autoradiographic analysis of 5HT,, receptors in ad- cific decreases in indices of 5-HT metabolism, while stressful jacent sections from the same animals indicated a simul- procedures, which raise corticosteroid levels, produce corre- taneous increase in 5-HT,, binding throughout the sponding increases in 5-HT turnover (Curzon et al., 1972; Van hippocampus in response to ADX.
    [Show full text]
  • Focus on Moclobemide
    REVIEW PAPERS Biochemistry and Pharmacology of Reversible Inhibitors of MAO-A Agents: Focus on Moclobemide N.P.V. Nair, M.D., S.K. Ahmed, M.D., N.M.K. Ng Ying Kin, Ph.D. Douglas Hospital Research Centre, Verdun, Quebec Submitted: December 21, 1992 Accepted: August 10, 1993 Moclobemide, p-chloro-N-[morpholinoethyl]benzamide, is a prototype of RIMA (reversible inhibitor of MAO-A) agents. The compound possesses antidepressant efficacy that is comparable to that of tricyclic and polycyclic antidepressants. In humans, moclobemide is rapidly absorbed after a single oral administration and maximum concentration in plasma is reached within an hour. It is moderately to markedly bound to plasma proteins. MAO-A inhibition rises to 80% within two hours; the duration of MAO inhibition is usually between eight and ten hours. The activity of MAO is completely reestablished within 24 hours of the last dose, so that a quick switch to another antidepressant can be safely undertaken if clinical circumstances demand. RIMAs are potent inhibitors ofMAO-A in the brain; they increase the free cytosolic concentrations ofnorepinephrine, serotonin and dopamine in neuronal cells and in synaptic vesicles. Extracellular concentrations of these monoamines also increase. In the case of moclobemide, increase in the level of serotonin is the most pronounced. Moclobemide administration also leads to increased monoamine receptor stimu- lation, reversal of reserpine induced behavioral effects, selective depression of REM sleep, down regulation of 3-adrenoceptors and increases in plasma prolactin and growth hormone levels. It reduces scopolamine-induced performance decrement and alcohol induced performance deficit which suggest a neuroprotective role.
    [Show full text]
  • Synthesis, 142 Termination of Action, 142–143 See Also Serotonin
    Cambridge University Press 978-1-107-02598-1 — Stahl's Essential Psychopharmacology 4th Edition Index More Information Index 5HT (5-hydroxytryptamine) acetaminophen, 340 alpha 1 adrenergic antagonists synthesis, 142 acetylation of histones, 24 atypical antipsychotics, 173 termination of action, 142–143 acetylcholine, 5 alpha 2 antagonists, 317–322 See also serotonin. as brain’s own nicotine, 543 alpha 2 delta ligands 5HT1A receptor partial agonists basis for cholinesterase treatment as anxiolytics, 403–405 atypical antipsychotics, 156–159 of dementia, 522–528 alpha 2A adrenergic agonists vilazodone, 300–302 cholinergic pathways, 524 ADHD treatment, 495–499 5HT1B/D receptors cholinergic receptors, 523–528 alpha-melanocyte stimulating effects of atypical antipsychotics, precursors, 524 hormone (alpha-MSH), 565 159–160 acetylcholine transporters, 523 alprazolam, 5, 49 terminal autoreceptors, 159–160 acetylcholine vesicular transporter, 29 Alzheimer’s dementia, 504 5HT2A receptor antagonists, 318 acetylcholinesterase, 46, 522–525 and psychosis, 79 atypical antipsychotic actions, Adapin, 342 Alzheimer’s disease 142–156 adenosine antagonist acetylcholine as target for current effects on dopamine D2 receptors, caffeine, 469 symptomatic treatment, 522–527 151–156 adiponectin, 565 aggressive and hostile symptoms, 85 effects on extrapyramidal adolescents amyloid as target of disease- symptoms, 150 bipolar disorder, 386 modifying treatment, 520–523 effects on prolactin levels, mania, 386 amyloid cascade hypothesis, 150–151 mood stabilizer selection,
    [Show full text]
  • Alteration of Monoamine Receptor Activity and Glucose Metabolism in Pediatric Patients with Anticonvulsant-Induced Cognitive Impairment
    Alteration of Monoamine Receptor Activity and Glucose Metabolism in Pediatric Patients with Anticonvulsant-Induced Cognitive Impairment Yuankai Zhu*1–4, Jianhua Feng*5, Jianfeng Ji*1–4, Haifeng Hou1–4, Lin Chen1–4, Shuang Wu1–4, Qing Liu1–4, Qiong Yao1–4, Peizhen Du1–4, Kai Zhang1–4, Qing Chen1–4, Zexin Chen6, Hong Zhang1–4, and Mei Tian1–4 1Department of Nuclear Medicine, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, China; 2Zhejiang University Medical PET Centre, Zhejiang University, Hangzhou, China; 3Institute of Nuclear Medicine and Molecular Imaging, Zhejiang University, Hangzhou, China; 4Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China; 5Department of Paediatrics, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, China; and 6Department of Clinical Epidemiology & Biostatistics, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, China children with epilepsy is timely and imperative (1). Cognitive A landmark study from the Institute of Medicine reported that the impairment is the most common side effect of anticonvulsants, assessment of cognitive difficulties in children with epilepsy is timely and the risk may accumulate when anticonvulsants are combined and imperative. Anticonvulsant-induced cognitive impairment could (2). Particularly, the developing brains of pediatric patients appear influence the quality of life more than seizure itself in patients. to be particularly sensitive to the cognitive adverse effects of Although the
    [Show full text]
  • DRUGS for MOOD DISORDERS Psy15 (1)
    DRUGS FOR MOOD DISORDERS Psy15 (1) Drugs for Mood Disorders Last updated: April 24, 2019 ANTIDEPRESSANTS (S. THYMOLEPTICS) ................................................................................................. 1 I. TRICYCLIC ANTIDEPRESSANTS (TCAS) .............................................................................................. 1 Pharmacokinetics ................................................................................................................... 1 Mechanism of Action ............................................................................................................ 2 Indications ............................................................................................................................. 2 Side Effects ............................................................................................................................ 2 II. MONOAMINE OXIDASE INHIBITORS (MAOIS) ................................................................................... 2 Pharmacokinetics ................................................................................................................... 2 Mechanism of Action ............................................................................................................ 2 Indications ............................................................................................................................. 3 Side Effects ...........................................................................................................................
    [Show full text]