DOCSLIB.ORG

A Nonlinear Relationship Between Cerebral Serotonin Transporter And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Nonlinear Relationship Between Cerebral Serotonin Transporter And The Journal of Neuroscience, March 3, 2010 • 30(9):3391–3397 • 3391 Cellular/Molecular A Nonlinear Relationship between Cerebral Serotonin Transporter and 5-HT2A Receptor Binding: An In Vivo Molecular Imaging Study in Humans David Erritzoe,1,3 Klaus Holst,3,4 Vibe G. Frokjaer,1,3 Cecilie L. Licht,1,3 Jan Kalbitzer,1,3 Finn Å. Nielsen,3,5 Claus Svarer,1,3 Jacob Madsen,2 and Gitte M. Knudsen1,3 1Neurobiology Research Unit and 2PET and Cyclotron Unit, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark, 3Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark, 4Department of Biostatistics, University of Copenhagen, DK-2200 Copenhagen, Denmark, and 5DTU Informatics, Technical University of Denmark, DK-2800 Lyngby, Denmark Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Withintheserotonintransmittersystem,boththepostsynapticallylocatedserotonin2A(5-HT2A )receptorandthepresynapticserotonin transporter (SERT) are sensitive to chronic changes in cerebral 5-HT levels. Additionally, experimental studies suggest that alterations in either the 5-HT2A receptor or SERT level can affect the protein level of the counterpart. The aim of this study was to explore the covariation betweencerebral5-HT2A receptorandSERT invivointhesamehealthyhumansubjects.Fifty-sixhealthyhumansubjectswithameanage of 36 Ϯ 19 years were investigated. The SERT binding was imaged with [ 11C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)- 18 benzonitrile (DASB) and 5-HT2A receptor binding with [ F]altanserin using positron emission tomography. Within each individual, a regionalintercorrelationforthevariousbrainregionswasseenwithbothmarkers,mostnotablyfor5-HT2A receptorbinding.Aninverted U-shaped relationship between the 5-HT2A receptor and the SERT binding was identified. The observed regional intercorrelation for both the 5-HT2A receptor and the SERT cerebral binding suggests that, within the single individual, each marker has a set point adjusted through a common regulator. A quadratic relationship between the two markers is consistent with data from experimental studies of the effect on SERT and 5-HT2A receptor binding of chronic changes in 5-HT levels. That is, the observed association between the 5-HT2A receptor and SERT binding could be driven by the projection output from the raphe nuclei, but other explanations are also at hand. Introduction well as on serotonergic axons and nerve terminals (Zhou et al., Central serotonin [5-hydroxytryptamine (5-HT)] function has a 1998, 2000). profound role in the normal brain function, in which it modu- The 5-HT neurotransmission is mediated through different lates mood, sex, appetite, sleep, memory, emotion, and endocrine postsynaptic receptors such as the 5-HT2A. This receptor is het- responses. Serotonin is synthesized and released by neurons that erogeneously distributed with high receptor concentrations in have their cell bodies in the raphe nuclei in the brainstem, and the several cortical areas (Pazos et al., 1987; Adams et al., 2004; Varnas et effect of its release is mediated through at least 15 presynaptic and al., 2004) in which they are located primarily postsynaptically postsynaptic receptors. (and perisynaptically) (Miner et al., 2003). The cerebral 5-HT2A The presynaptically located serotonin transporter (SERT) is receptors are mainly expressed on glutamatergic pyramidal neu- crucial for the regulation of 5-HT transmission because it con- rons, cholinergic neurons, and GABAergic interneurons (Morilak et trols the 5-HT availability at the site of the postsynaptic receptors al., 1994; Santana et al., 2004), and, in most areas of the forebrain, by high-affinity reuptake of released 5-HT (Blakely et al., 1994). regional variations in their density correspond closely to the The SERT protein is expressed in high density in dorsal and 5-HT axon innervation (Blue et al., 1988). median raphe nuclei, caudate, putamen, and thalamus but in Cerebral 5-HT2A receptors and SERT protein levels both re- relatively low densities in cortex (Varnas et al., 2004). More spe- spond to chronic changes in 5-HT levels. In vitro autoradiogra- cifically, SERTs are localized on cell bodies in the raphe nucleus as phy and homogenate binding experiments in rats suggest that a decrease in SERT binding levels occur after pharmacologically induced chronic extracellular 5-HT depletion in two (Rattray et Received June 16, 2009; revised Nov. 2, 2009; accepted Dec. 24, 2009. al., 1996; Rothman et al., 2003) of three studies (no change seen in The study was sponsored by The Danish Medical Research Council, H:S (Copenhagen Hospital Cooperation) the study by Dewar et al., 1992). Chronically elevated extracellu- Research Council, Copenhagen University Hospital, and The Lundbeck Foundation. lar 5-HT levels have usually been achieved by chronic treatment The authors declare no competing financial interests. with the specific selective serotonin reuptake inhibitor (SSRI) Correspondence should be addressed to Dr. David Erritzoe, Neurobiology Research Unit 9201, Copenhagen Uni- versity Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail: [email protected]. compounds sertraline, citalopram, and paroxetine, and, in 10 DOI:10.1523/JNEUROSCI.2852-09.2010 (Kovachich et al., 1992; Pineyro et al., 1994; Benmansour et al., Copyright © 2010 the authors 0270-6474/10/303391-07$15.00/0 1999; Horschitz et al., 2001; Benmansour et al., 2002; Gould et al., • 3392 • J. Neurosci., March 3, 2010 • 30(9):3391–3397 Erritzoe et al. SERT and 5-HT2A Receptor Binding in Humans 2003, 2006; Rossi et al., 2008) of 15 experimental settings (no conducted according to DeGrado et al. (1994). All subjects were scanned change reported in the studies by Graham et al., 1987; Kovachich in a resting state. 18 et al., 1992; Cheetham et al., 1993; Gobbi et al., 1997; Gould et al., For [ F]altanserin, subjects underwent a 40 min scan under tracer steady-state conditions as described by Pinborg et al. (2003). [ 18F]altan- 2006), decreased SERT levels have been found. It can be argued, Ϯ ␮ however, that chronic blockade of the SERT may lead to regula- serin was produced with a mean specific activity of 58 36 GBq/ mol (range, 10–182 GBq/␮mol), and subjects received 297 Ϯ 52 MBq (range, tion of its expression and that the primary cause for the SERT 204–437 MBq), corresponding to 7.4 Ϯ 5.4 nmol [ 18F]altanserin. For downregulation is unrelated to 5-HT levels. However, support [ 11C]DASB, a dynamic 90-min-long emission recording was initiated for a direct 5-HT effect comes from monoamine oxidase A during intravenous injection during 12 s of 485 Ϯ 86 MBq (range, 279– knock-out mice. These mice have increased extracellular 5-HT 601 MBq) [ 11C]DASB, with specific activity of 29 Ϯ 16 GBq/␮mol levels and reduced SERT levels (Evrard et al., 2002). For the (range, 9–82 GBq/␮mol). The two PET scans obtained for each individ- Ϯ 5-HT2A receptors, moderate 5-HT depletion results in an inverse ual were acquired with an average gap between scans of 104 200 d correlation between 5-HT and 5-HT2A receptor levels (Heal et al., (range, 0–793 d). 18 1985; Cahir et al., 2007), and chronically increased 5-HT levels The outcome parameter for [ F]altanserin binding was the binding potential of specific tracer binding (BPP). Cerebellum was used as a ref- after SSRI treatment results in a reduction in 5-HT2A receptor binding (Nelson et al., 1989; Cowen, 1990; Maj et al., 1996; erence region because it represents nonspecific binding only (Pinborg et al., 2003). In steady state, BP is defined as follows: Gunther et al., 2008; Licht et al., 2009). The latter observation has P also been made in humans; chronic (Spigset and Mjorndal, 1997; C Ϫ C B ϭ VOI ND ϭ ϫ max Meyer et al., 2001) but not acute (Pinborg et al., 2004) SSRI BPP fP , CP Kd (ml/ml) treatment decreases cortical 5-HT2A receptor binding. Likewise, acute tryptophan depletion in humans, resulting in a transient where CVOI and CND are steady-state mean count density in the volume reduction in cerebral 5-HT levels, does not alter cerebral SERT of interest (VOI) and in the reference region, respectively, CP is the binding (Praschak-Rieder et al., 2004, 2005; Talbot et al., 2005). steady-state activity of nonmetabolized tracer in plasma, fP is the free In the absence of competition effects, it is unlikely that acutely fraction of radiotracer, Bmax is the density of receptor sites available for induced alterations in cerebral 5-HT levels alone would lead to tracer binding, and Kd is the affinity constant of the radiotracer to the immediate changes in SERT binding as assessed with in vivo im- receptor. The outcome parameter of the [ 11C]DASB binding is the non- aging. Protein expression and trafficking are considered to be displaceable binding potential, designated BPND. We used a modified Ͼ reference tissue model designed specifically for quantification of more long-term processes, and, accordingly, 5 d of 5-HT de- 11 pletion is required to see a downregulation in SERT binding (Rattray [ C]DASB (MRTM/MRTM2) as described and evaluated by Ichise et al. (2003) using the software PMOD version 2.9 (PMOD Technologies). For et al., 1996). further details about [ 18F]altanserin and [ 11C]DASB imaging and quan- The aim of this study was, for the first time, to investigate the tification, please see (Erritzoe et al., 2009) and (Frokjaer et al., 2009), in vivo relationship between SERT and 5-HT2A receptor binding respectively. in a large group of healthy human subjects using the selective Magnetic resonance imaging. Magnetic resonance imaging (MRI) of positron emission tomography (PET) radioligands [ 11C]3-amino- the brain was acquired on a Siemens Magnetom Trio3TMRscanner 4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) with an eight-channel head coil (In Vivo Clinical Research). High- and [ 18F]altanserin. Provided that in normal healthy individuals resolution three-dimensional T1-weighted, sagittal, magnetization pre- there is some interindividual variation in the dorsal raphe output pared rapid gradient echo scans of the head and T2-weighted scans of the whole brain were acquired.
Load more

Recommended publications
  • TABLE 1 Studies of Antagonist Activity in Constitutively Active
    TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic
    [Show full text]
  • Effects of Stress-Induced Depression on Parkinson's Disease
    Effects of stress-induced depression on Parkinson’s disease symptomatology A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Ph.D.) in the Graduate Program in Neuroscience of the College of Medicine 2011 By Ann Marie Hemmerle B.S., University of Dayton Advisor: Kim B. Seroogy, Ph.D. Committee Chair: Neil Richtand, M.D., Ph.D. James P. Herman, Ph.D. Kathy Steece-Collier, Ph.D. Aaron Johnson, Ph.D. Abstract Parkinson’s disease (PD) is a chronic neurodegenerative disorder that primarily affects dopaminergic neurons of the nigrostriatal pathway resulting in debilitating motor symptoms. Parkinson’s patients also have a high risk of comorbid depression, though this aspect of the disorder is less well studied. Understanding the underlying pathology of the comorbidity is important in improving clinical treatments and the quality of life for PD patients. To address this issue, we have developed a new model combining the unilateral striatal 6-hydroxydopamine lesion model of PD with the chronic variable stress model (CVS) of depression. Dysfunction of the hypothalamic-pituitary-adrenal axis and its relationship to depression symptomatology is well established. Stress dysfunction may also have a role in the etiology of preclinical PD non- motor symptoms, and later in the course of the disease, may worsen motor symptoms. The combined model allows us to test the hypothesis that experimental depression exacerbates PD symptoms and to ascertain the mechanisms behind the increased neuronal loss. In the first study, we examined several temporal paradigms of the combined model.
    [Show full text]
  • Exaggerated 5-HT1A but Normal 5-HT2A Receptor Activity in Individuals Ill with Anorexia Nervosa Ursula F
    Exaggerated 5-HT1A but Normal 5-HT2A Receptor Activity in Individuals Ill with Anorexia Nervosa Ursula F. Bailer, Guido K. Frank, Shannan E. Henry, Julie C. Price, Carolyn C. Meltzer, Chester A. Mathis, Angela Wagner, Laura Thornton, Jessica Hoge, Scott K. Ziolko, Carl R. Becker, Claire W. McConaha, and Walter H. Kaye Background: Many studies have found disturbances of serotonin (5-HT) activity in anorexia nervosa (AN). Because little is known about 5-HT receptor function in AN, positron emission tomography (PET) imaging with 5-HT receptor-specific radioligands was used to character- ize 5-HT1A and 5-HT2A receptors. Methods: Fifteen women ill with AN (ILL AN) were compared with 29 healthy control women (CW); PET and [11C]WAY100635 were used to assess binding potential (BP) of the 5-HT1A receptor, and [18F]altanserin was used to assess postsynaptic 5-HT2A receptor BP. [15O] water and PET were used to assess cerebral blood flow. Results: The ILL AN women had a highly significant (30%–70%) increase in [11C]WAY100635 BP in prefrontal and lateral orbital frontal regions, mesial and lateral temporal lobes, parietal cortex, and dorsal raphe nuclei compared with CW. The [18F]altanserin BP was normal in ILL AN but was positively and significantly related to harm avoidance in suprapragenual cingulate, frontal, and parietal regions. Cerebral blood flow was normal in ILL AN women. Conclusions: Increased activity of 5-HT1A receptor activity may help explain poor response to 5-HT medication in ILL AN. This study extends data suggesting that 5-HT function, and, specifically, the 5-HT2A receptor, is related to anxiety in AN.
    [Show full text]
  • Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: a PET Study in Conscious Monkeys
    Neuropsychopharmacology (2013) 38, 2666–2674 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys 1 1 1 1 1 Shigeyuki Yamamoto , Hiroyuki Ohba , Shingo Nishiyama , Norihiro Harada , Takeharu Kakiuchi , 1 ,2 Hideo Tsukada and Edward F Domino* 1 2 Central Research Laboratory, Hamamatsu Photonics KK, Hamakita, Japan; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys 11 underwent four positron emission tomography measurements with [ C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzoni- 11 trile ([ C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a 11 dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT1A-R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [11C]DASB. No significant changes were observed in either 5-HT -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased 1A serotonin levels in the extracellular fluid of the prefrontal cortex.
    [Show full text]
  • Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation
    www.sciencemag.org/cgi/content/full/327/5963/348/DC1 Supporting Online Material for Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation Jason Rihel,* David A. Prober, Anthony Arvanites, Kelvin Lam, Steven Zimmerman, Sumin Jang, Stephen J. Haggarty, David Kokel, Lee L. Rubin, Randall T. Peterson, Alexander F. Schier* *To whom correspondence should be addressed. E-mail: [email protected] (A.F.S.); [email protected] (J.R.) Published 15 January 2010, Science 327, 348 (2010) DOI: 10.1126/science.1183090 This PDF file includes: Materials and Methods SOM Text Figs. S1 to S18 Table S1 References Supporting Online Material Table of Contents Materials and Methods, pages 2-4 Supplemental Text 1-7, pages 5-10 Text 1. Psychotropic Drug Discovery, page 5 Text 2. Dose, pages 5-6 Text 3. Therapeutic Classes of Drugs Induce Correlated Behaviors, page 6 Text 4. Polypharmacology, pages 6-7 Text 5. Pharmacological Conservation, pages 7-9 Text 6. Non-overlapping Regulation of Rest/Wake States, page 9 Text 7. High Throughput Behavioral Screening in Practice, page 10 Supplemental Figure Legends, pages 11-14 Figure S1. Expanded hierarchical clustering analysis, pages 15-18 Figure S2. Hierarchical and k-means clustering yield similar cluster architectures, page 19 Figure S3. Expanded k-means clustergram, pages 20-23 Figure S4. Behavioral fingerprints are stable across a range of doses, page 24 Figure S5. Compounds that share biological targets have highly correlated behavioral fingerprints, page 25 Figure S6. Examples of compounds that share biological targets and/or structural similarity that give similar behavioral profiles, page 26 Figure S7.
    [Show full text]
  • Brain Imaging
    Publications · Brochures Brain Imaging A Technologist’s Guide Produced with the kind Support of Editors Fragoso Costa, Pedro (Oldenburg) Santos, Andrea (Lisbon) Vidovič, Borut (Munich) Contributors Arbizu Lostao, Javier Pagani, Marco Barthel, Henryk Payoux, Pierre Boehm, Torsten Pepe, Giovanna Calapaquí-Terán, Adriana Peștean, Claudiu Delgado-Bolton, Roberto Sabri, Osama Garibotto, Valentina Sočan, Aljaž Grmek, Marko Sousa, Eva Hackett, Elizabeth Testanera, Giorgio Hoffmann, Karl Titus Tiepolt, Solveig Law, Ian van de Giessen, Elsmarieke Lucena, Filipa Vaz, Tânia Morbelli, Silvia Werner, Peter Contents Foreword 4 Introduction 5 Andrea Santos, Pedro Fragoso Costa Chapter 1 Anatomy, Physiology and Pathology 6 Elsmarieke van de Giessen, Silvia Morbelli and Pierre Payoux Chapter 2 Tracers for Brain Imaging 12 Aljaz Socan Chapter 3 SPECT and SPECT/CT in Oncological Brain Imaging (*) 26 Elizabeth C. Hackett Chapter 4 Imaging in Oncological Brain Diseases: PET/CT 33 EANM Giorgio Testanera and Giovanna Pepe Chapter 5 Imaging in Neurological and Vascular Brain Diseases (SPECT and SPECT/CT) 54 Filipa Lucena, Eva Sousa and Tânia F. Vaz Chapter 6 Imaging in Neurological and Vascular Brain Diseases (PET/CT) 72 Ian Law, Valentina Garibotto and Marco Pagani Chapter 7 PET/CT in Radiotherapy Planning of Brain Tumours 92 Roberto Delgado-Bolton, Adriana K. Calapaquí-Terán and Javier Arbizu Chapter 8 PET/MRI for Brain Imaging 100 Peter Werner, Torsten Boehm, Solveig Tiepolt, Henryk Barthel, Karl T. Hoffmann and Osama Sabri Chapter 9 Brain Death 110 Marko Grmek Chapter 10 Health Care in Patients with Neurological Disorders 116 Claudiu Peștean Imprint 126 n accordance with the Austrian Eco-Label for printed matters.
    [Show full text]
  • Personalized Treatment of Alcohol Dependence
    Curr Psychiatry Rep DOI 10.1007/s11920-012-0296-5 SUBSTANCE USE AND RELATED DISORDERS (JR MCKAY, SECTION EDITOR) Personalized Treatment of Alcohol Dependence Henry R. Kranzler & James R. McKay # Springer Science+Business Media, LLC 2012 Abstract Pharmacogenetic and adaptive treatment approaches Ondansetron . Sertraline . Adaptive trial designs . can be used to personalize care for alcohol-dependent patients. Adaptive protocol . Stepped care . Treatment algorithm Preliminary evidence shows that variation in the gene encoding the μ-opioid receptor moderates the response to naltrexone when used to treat alcohol dependence. Studies have also shown moderating effects of variation in the gene encoding Introduction the serotonin transporter on response to serotonergic treatment of alcohol dependence. Adaptive algorithms that modify alco- Traditionally, diagnostic tests and medical treatments have hol treatment based on patients’ progress have also shown been developed and evaluated using group data, a “one-size promise. Initial response to outpatient treatment appears to be fits all” approach that leaves little room for individual variation a particularly important in the selection of optimal continuing [1]. Personalized medicine, which uses individual features to care interventions. In addition, stepped-care algorithms can diagnose and treat disease, is of growing interest, having reduce the cost and burden of treatment while maintaining good produced notable successes in oncology and cardiology [2•, outcomes. Finally, matching treatment to specific problems 3]. To date, there have been fewer advances in the personalized present at intake or that emerge during treatment can also diagnosis and treatment of addictive disorders. However, on- improve outcomes. Although all of these effects require repli- going developments in genetics and pharmacogenetics and in cation and further refinement, the future of personalized care for the use of adaptive trial designs offer great potential to extend alcohol dependence appears bright.
    [Show full text]
  • Test–Retest Variability of Serotonin 5-HT2A Receptor Binding Measured with Positron Emission Tomography and [18F]Altanserin in the Human Brain
    SYNAPSE 30:380–392 (1998) Test–Retest Variability of Serotonin 5-HT2A Receptor Binding Measured With Positron Emission Tomography and [18F]Altanserin in the Human Brain GWENN S. SMITH,1,2* JULIE C. PRICE,2 BRIAN J. LOPRESTI,2 YIYUN HUANG,2 NORMAN SIMPSON,2 DANIEL HOLT,2 N. SCOTT MASON,2 CAROLYN CIDIS MELTZER,1,2 ROBERT A. SWEET,1 THOMAS NICHOLS,2 DONALD SASHIN,2 AND CHESTER A. MATHIS2 1Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 2Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania KEY WORDS positron emission tomography (PET); serotonin receptor; 5-HT2A; imaging ABSTRACT The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test–retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) 18 studies of the serotonin 5-HT2A receptor. Two high specific activity [ F]altanserin PET studies were performed in normal control subjects (n ϭ 8) on two separate days (2–16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum.
    [Show full text]
  • Thesis (1.852Mb)
    From DEPARTMENT OF CLINICAL NEUROSCIENCE Karolinska Institutet, Stockholm, Sweden PET STUDIES ON THE MECHANISMS OF ACTION OF ANTIDEPRESSANT AND ANTIPSYCHOTIC DRUGS Kai-Chun Yang Stockholm 2017 Cover illusion: Parasagittal PET-section of a nonhuman primate brain showing regional reductions of 11 [ C]AZ10419369 binding to the 5-HT1B receptor after administration of vortioxetine, a novel antidepressant. All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by E-Print AB 2017 © Kai-Chun Yang, 2017 ISBN 978-91-7676-786-3 PET Studies on the Mechanisms of Action of Antidepressant and Antipsychotic Drugs THESIS FOR DOCTORAL DEGREE (Ph.D.) By Kai-Chun Yang Principal Supervisor: Opponent: Dr Sjoerd J. Finnema Professor Yasuyoshi Watanabe Karolinska Institutet RIKEN Department of Clinical Neuroscience Center for Life Science Technologies Co-supervisor(s): Examination Board: Professor Lars Farde Professor Sven Ove Ögren Karolinska Institutet Karolinska Institutet Department of Clinical Neuroscience Department of Neuroscience Professor Christer Halldin Professor Hans Ågren Karolinska Institutet University of Gothenburg Department of Clinical Neuroscience Institute of Neuroscience and Physiology Dr Akihiro Takano Professor Mark Lubberink Karolinska Institutet Uppsala University Department of Clinical Neuroscience Department of Surgical Sciences In memory of my father, 楊正宗 (Yang, Cheng-Tsung), 1945-2011 “I couldn't reduce it to the freshman level. That means we don't really understand it.” Richard Feynman, 1918-1988 ABSTRACT Positron emission tomography (PET) is a non-invasive molecular imaging technique suitable for examination of neurochemical biomarkers in the living brain. Among these applications, PET studies are used to facilitate the development of novel psychotropic drugs.
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]
  • NIH Public Access Author Manuscript Mol Psychiatry
    NIH Public Access Author Manuscript Mol Psychiatry. Author manuscript; available in PMC 2013 January 03. Published in final edited form as: Mol Psychiatry. 2012 July ; 17(7): 694–704. doi:10.1038/mp.2011.50. Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 $watermark-text(Tph2) $watermark-text loss-of-function $watermark-text mice JPR Jacobsen1, WB Siesser1, BD Sachs1, S Peterson1, MJ Cools1, V Setola2, JHA Folgering3, G Flik3, and MG Caron1,4 1Department of Cell Biology, Duke University, Durham, NC, USA 2Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA 3BrainsOnline, Groningen, The Netherlands 4Department of Neurobiology, Duke University Medical Center, Durham, NC, USA Abstract Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HTExt). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT1A receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT2A receptors are increased in the Tph2 knockin mice.
    [Show full text]
  • Diamandis Thesis
    !"!#$ CHEMICAL GENETIC INTERROGATION OF NEURAL STEM CELLS: PHENOTYPE AND FUNCTION OF NEUROTRANSMITTER PATHWAYS IN NORMAL AND BRAIN TUMOUR INITIATING NEURAL PRECUSOR CELLS by Phedias Diamandis A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy. Department of Molecular Genetics University of Toronto © Copyright by Phedias Diamandis 2010 Phenotype and Function of Neurotransmitter Pathways in Normal and Brain Tumor Initiating Neural Precursor Cells Phedias Diamandis Doctor of Philosophy Department of Molecular Genetics University of Toronto 2010 &'(!)&*!% The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain brings promise for the treatment of neurological diseases and has yielded new insight into brain cancer. The complete repertoire of signaling pathways that governs these cells however remains largely uncharacterized. This thesis describes how chemical genetic approaches can be used to probe and better define the operational circuitry of the NSC. I describe the development of a small molecule chemical genetic screen of NSCs that uncovered an unappreciated precursor role of a number of neurotransmitter pathways commonly thought to operate primarily in the mature central nervous system (CNS). Given the similarities between stem cells and cancer, I then translated this knowledge to demonstrate that these neurotransmitter regulatory effects are also conserved within cultures of cancer stem cells. I then provide experimental and epidemiologically support for this hypothesis and suggest that neurotransmitter signals may also regulate the expansion of precursor cells that drive tumor growth in the brain. Specifically, I first evaluate the effects of neurochemicals in mouse models of brain tumors. I then outline a retrospective meta-analysis of brain tumor incidence rates in psychiatric patients presumed to be chronically taking neuromodulators similar to those identified in the initial screen.
    [Show full text]