DOCSLIB.ORG

Dopamine Reuptake Inhibitors in Parkinson's Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Dopamine Reuptake Inhibitors in Parkinson's Disease 1521-0103/357/3/562–569$25.00 http://dx.doi.org/10.1124/jpet.116.232371 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 357:562–569, June 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Minireviews Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of Nonhuman Primate Studies and Clinical Trials Philippe Huot,1 Susan H. Fox, and Jonathan M. Brotchie The Krembil Institute (P.H., S.H.F., J.M.B.) and Movement Disorder Clinic (P.H., S.H.F.), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; and Division of Neurology, University of Toronto, Toronto, Ontario, Canada (P.H., S. Downloaded from H.F.) Received January 21, 2016; accepted April 6, 2016 ABSTRACT Striatal dopamine deficiency is the core feature of the pathology of as they increase synaptic dopamine levels, dopamine transporter jpet.aspetjournals.org Parkinson’s disease (PD), and dopamine replacement with L-3,4- (DAT) inhibitors, whether they are selective or have actions on dihydroxyphenylalanine (L-DOPA) is the mainstay of PD treatment. noradrenaline or serotonin transporters, theoretically represent an Unfortunately, chronic L-DOPA administration is marred by the attractive way to alleviate parkinsonism per se and potentially emergence of dyskinesia and wearing-off. Alternatives to L-DOPA enhance L-DOPA antiparkinsonian action (provided that sufficient for alleviation of parkinsonism are of interest, although none can dopamine terminals remain within the striatum). Several non- match the efficacy of L-DOPA to date. Catechol-O-methyltrans- human primate studies and clinical trials have been performed to ferase and monoamine oxidase inhibitors are currently used to evaluate the potential of DAT inhibitors for PD. In this article, we alleviate wearing-off, but they do not increase “on-time” without review nonhuman primate studies and clinical trials, we summa- at ASPET Journals on September 29, 2021 exacerbating dyskinesia. Alternate approaches to dopamine re- rize the current knowledge of DAT inhibitors in PD, and we placement in parkinsonism generally (and to wearing-off and propose a hypothesis as to how tailoring the selectivity of DAT dyskinesia, specifically) are therefore urgently needed. Inasmuch inhibitors might maximize the benefits of DAT inhibition in PD. Introduction a complex issue (Fox and Lang, 2014), and whether to initiate therapy with a DOPA-sparing approach or L-DOPA has been an ’ Parkinson s disease (PD) is a neurodegenerative disorder in area of intense research recently (Cilia et al., 2014; Gray et al., which striatal dopamine levels are diminished (Hornykiewicz 2014). Therapies for the wearing-off phenomenon remain limited and Kish, 1987). Treatment with the dopamine precursor L-3,4- and essentially consist of inhibiting catechol-O-methyltransferase dihydroxyphenylalanine (L-DOPA) has been the mainstay of PD and MAO-B, the enzymes responsible for dopamine degradation therapy for the past 4 decades (Fahn, 2008). Unfortunately, (Parkinson Study Group, 2005; Rascol et al., 2005). However, chronic therapy with L-DOPA leads to the development of motor it seems to be very difficult to extend the duration of L-DOPA complications, including a shortening of duration of benefit, antiparkinsonian benefit (i.e., alleviate wearing-off) without wearing-off, and abnormal involuntary movements (dyskinesia) exacerbating dyskinesia; when catechol-O-methyltransferase (Hely et al., 2005). and MAO-B inhibitors are used as adjunct therapy, the extra There are several treatment options for early PD, including “on-time” gained is on-time with dyskinesia (Parkinson Study L-DOPA, dopamine agonists, amantadine, and monoamine Group, 2005; Rascol et al., 2005). oxidase type B (MAO-B) inhibitors. Treatment of early PD is Another potential approach to alleviate parkinsonian dis- ability and wearing-off lies in increasing the time spent by This research was supported by the Cure Parkinson Trust and the Krembil dopamine in the synaptic cleft and maximizing its chances of Neuroscience Fund. P.H. was supported by fellowships from the Edmond J. Safra Philanthropic Foundation, the Parkinson Society Canada, and the interaction with postsynaptic dopaminergic receptors; this Canadian Institutes of Health Research. could be achieved by preventing the reuptake of dopamine into 1Current affiliation: Division of Neurology, Department of Pharmacology, Montreal University Health Centre, Montreal, Quebec, Canada. the presynaptic neuron by the dopamine transporter (DAT). dx.doi.org/10.1124/jpet.116.232371. By the same mechanism, blocking dopamine reuptake might ABBREVIATIONS: 5-HT, serotonin; BTS-74,398, 1-([1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone; DAT, dopamine transporter; L-DOPA, L-3,4-dihydroxyphenylalanine; GBR-12,909, 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride; MAO-B, monoamine oxidase type B; MDMA, 3,4-methylenedioxymethamphetamine; MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; NAT, noradrenaline transporter; PD, Parkinson’s disease; SERT, serotonin transporter; UWA-101, 2-(1,3-benzodioxol-5-yl)-1- cyclopropyl-N-methylethanamine. 562 Dopamine Reuptake Inhibitors in Parkinson’s Disease 563 also exert an antiparkinsonian action as monotherapy. These selective DAT inhibitors have little effect on L-DOPA antipar- theoretical antiparkinsonian benefits form the rationale un- kinsonian efficacy and L-DOPA–induced dyskinesia. derlying the potential use of DAT inhibitors in PD. Many DAT inhibitors have been identified and span a spectrum of Dual DAT and NAT Inhibitors selectivity for DAT over other monoamine transporters; the pharmacology of these was recently reviewed in detail else- Brasofensine, bupropion, methylphenidate, and nomifen- where (Huot et al., 2015). sine are dual DAT and NAT inhibitors (with a DAT/NAT ratio In this article, we review the literature on selective and between 0.5 and 4; Huot et al., 2015) and have been studied as nonselective DAT inhibitors, their antiparkinsonian effect as potential therapies for PD. monotherapy, and their effects on on-time and dyskinesia as In the MPTP-lesioned marmoset, monotherapy with adjunct therapy. We also propose a hypothesis as to how the brasofensine reversed parkinsonian disability without elicit- pharmacoselectivity of DAT inhibitors might be best tailored ing dyskinesia (Pearce et al., 1995), and adjunct therapy with to maximize benefit in PD. Throughout, we divide the mono- brasofensine enhanced the antiparkinsonian action of low- amine reuptake inhibitors based on their affinity for DATs, dose L-DOPA. Similarly, in the parkinsonian marmoset, mono- noradrenaline transporters (NATs), and serotonin trans- therapy with nomifensine significantly improved parkinso- porters (SERTs). As in a previous article (Huot et al., 2015), nian disability (Hansard et al., 2002b). In contrast, monotherapy we considered that a compound was selective for a transporter with bupropion had no effect on parkinsonian disability when its affinity for that transporter was greater than 10-fold (Hansard et al., 2002b). Therefore, on balance, it seems that Downloaded from its affinity for that of the other transporters. dual DAT/NAT inhibitors can be effective as antiparkinsonian Here, we review preclinical studies performed in the 1- molecules when administered as monotherapy to the parkinso- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–lesioned nian monkey and, based on one single study, they appear nonhuman primate and clinical trials performed with pa- effective at enhancing the antiparkinsonian action of low- tients suffering from idiopathic PD (published prior to April dose L-DOPA. However, the nonhuman primate studies have not 2015). Studies performed in the 6-hydroxydopamine–lesioned addressed the important question of combining dual DAT/NAT jpet.aspetjournals.org rat were not included in our review because the vast majority inhibitors to high-dose L-DOPAinparkinsonianmonkeyswith of these studies employed rotational behavior as an endpoint, established dyskinesia. which can be difficult to interpret with respect to parkinson- Unlike selective DAT inhibitors, dual DAT/NAT inhibitors ism and dyskinesia benefits/liability (Marin et al., 2006). The have undergone clinical testing. In a small escalating-dose effects of the drugs discussed in the article are summarized in study, brasofensine did not enhance L-DOPA antiparkinso- Tables 1 and 2. nian action and did not alter L-DOPA–induced dyskinesia severity (Archibald, 2000; Cutler et al., 2000; Frackiewicz at ASPET Journals on September 29, 2021 Selective DAT Inhibitors et al., 2002). In a phase II trial, the administration of brasofensine as monotherapy to patients with recently di- GBR-12,909 (vanoxerine; 1-[2-[bis-(4-fluorophenyl)methoxy] agnosed PD initially improved parkinsonism, but the improve- ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride) and SEP- ment was not maintained after 2 weeks (Yu, 2000). In contrast 228,791 are selective DAT inhibitors (Huot et al., 2015) that with brasofensine, bupropion effectively alleviated parkinson- have been evaluated in the MPTP-lesioned monkey. To date, ism in a small add-on trial but exacerbated dyskinesia sever- neither GBR-12,909 nor SEP-228,791 has been studied in ity in one patient (Goetz et al., 1984). In two small trials, idiopathic PD. monotherapy with nomifensine effectively alleviated parkin- In the MPTP-lesioned common marmoset, acute challenge
Load more

Recommended publications
  • (Ssris) SEROTONIN and NOREPHINEPHRINE REUPTAKE INHIBITORS DOPAMINE and NOREPINEPHRINE RE
    VA / DOD DEPRESSION PRACTICE GUIDELINE PROVIDER CARE CARD ANTIDEPRESSANT MEDICATION TABLE CARD 7 Refer to pharmaceutical manufacturer’s literature for full prescribing information SEROTONIN SELECTIVE REUPTAKE INHIBITORS (SSRIs) GENERIC BRAND NAME ADULT STARTING DOSE MAX EXCEPTION SAFETY MARGIN TOLERABILITY EFFICACY SIMPLICITY Citalopram Celexa 20 mg 60 mg Reduce dose Nausea, insomnia, Fluoxetine Prozac 20 mg 80 mg for the elderly & No serious systemic sedation, those with renal toxicity even after headache, fatigue Paroxetine Paxil 20 mg 50 mg or hepatic substantial overdose. dizziness, sexual AM daily dosing. failure Drug interactions may dysfunction Response rate = Can be started at Sertraline Zoloft 50 mg 200 mg include tricyclic anorexia, weight 2 - 4 wks an effective dose First Line Antidepressant Medication antidepressants, loss, sweating, GI immediately. Drugs of this class differ substantially in safety, tolerability and simplicity when used in patients carbamazepine & distress, tremor, warfarin. restlessness, on other medications. Can work in TCA (tricyclic antidepressant) nonresponders. Useful in agitation, anxiety. several anxiety disorders. Taper gradually when discontinuing these medications. SEROTONIN and NOREPHINEPHRINE REUPTAKE INHIBITORS GENERIC BRAND NAME ADULT STARTING DOSE MAX EXCEPTION SAFETY MARGIN TOLERABILITY EFFICACY SIMPLICITY Reduce dose Take with food. Venlafaxine IR Effexor IR 75 mg 375 mg Comparable to BID or TID for the elderly & No serious systemic SSRIs at low dose. dosing with IR. those with renal toxicity. Nausea, dry mouth, Response rate = Daily dosing or hepatic Downtaper slowly to Venlafaxine XR Effexor XR 75 mg 375 mg insomnia, anxiety, 2 - 4 wks with XR. failure prevent clinically somnolence, head- (4 - 7 days at Can be started at significant withdrawal ache, dizziness, ~300 mg/day) an effective dose Dual action drug that predominantly acts like a Serotonin Selective Reuptake inhibitor at low syndrome.
    [Show full text]
  • Selective Serotonin Reuptake Inhibitors, Fluoxetine and Paroxetine, Attenuate the Expression of the Established Behavioral Sensitization Induced by Methamphetamine
    Neuropsychopharmacology (2007) 32, 658–664 & 2007 Nature Publishing Group All rights reserved 0893-133X/07 $30.00 www.neuropsychopharmacology.org Selective Serotonin Reuptake Inhibitors, Fluoxetine and Paroxetine, Attenuate the Expression of the Established Behavioral Sensitization Induced by Methamphetamine 1 1 1 1 1 ,1 Yujiro Kaneko , Atsushi Kashiwa , Takashi Ito , Sumikazu Ishii , Asami Umino and Toru Nishikawa* 1 Section of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Yushima, Bunkyo-ku, Tokyo, Japan To obtain an insight into the development of a new pharmacotherapy that prevents the treatment-resistant relapse of psychostimulant- induced psychosis and schizophrenia, we have investigated in the mouse the effects of selective serotonin reuptake inhibitors (SSRI), fluoxetine (FLX) and paroxetine (PRX), on the established sensitization induced by methamphetamine (MAP), a model of the relapse of these psychoses, because the modifications of the brain serotonergic transmission have been reported to antagonize the sensitization phenomenon. In agreement with previous reports, repeated MAP treatment (1.0 mg/kg a day, subcutaneously (s.c.)) for 10 days induced a long-lasting enhancement of the increasing effects of a challenge dose of MAP (0.24 mg/kg, s.c.) on motor activity on day 12 or 29 of withdrawal. The daily injection of FLX (10 mg/kg, s.c.) or PRX (8 mg/kg, s.c.) from 12 to 16 days of withdrawal of repeated MAP administration markedly attenuated the ability of the MAP pretreatment to augment the motor responses to the challenge dose of the stimulant 13 days after the SSRI injection. The repeated treatment with FLX or PRX alone failed to affect the motor stimulation following the challenge of saline and MAP 13 days later.
    [Show full text]
  • Understanding the Structure-Function Relationships Between Monoamine Neurotransmitter Transporters and Their Cognate Ions and Ligands
    University of North Dakota UND Scholarly Commons Theses and Dissertations Theses, Dissertations, and Senior Projects January 2015 Understanding The trS ucture-Function Relationships Between Monoamine Neurotransmitter Transporters And Their ogC nate Ions And Ligands Bruce Felts Follow this and additional works at: https://commons.und.edu/theses Recommended Citation Felts, Bruce, "Understanding The trS ucture-Function Relationships Between Monoamine Neurotransmitter Transporters And Their Cognate Ions And Ligands" (2015). Theses and Dissertations. 1769. https://commons.und.edu/theses/1769 This Dissertation is brought to you for free and open access by the Theses, Dissertations, and Senior Projects at UND Scholarly Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UND Scholarly Commons. For more information, please contact [email protected]. UNDERSTANDING THE STRUCTURE-FUNCTION RELATIONSHIPS BETWEEN MONOAMINE NEUROTRANSMITTER TRANSPORTERS AND THEIR COGNATE IONS AND LIGANDS by Bruce F. Felts Bachelor of Science, University of Minnesota 2009 A dissertation Submitted to the Graduate Faculty of the University of North Dakota in partial fulfillment of the requirements for the degree of Doctor of Philosophy Grand Forks, North Dakota August 2015 Copyright 2015 Bruce Felts ii TABLE OF CONTENTS LIST OF FIGURES………………………………………………………………………... xii LIST OF TABLES……………………….………………………………………………… xv ACKNOWLEDGMENTS.…………………………………………………………….… xvi ABSTRACT.………………………………………………………………………….……. xviii CHAPTERS I. INTRODUCTION.………………………………………………………………… 1 The Solute Carrier Super-family of Proteins………………………………. 1 The Neurophysiologic Role of MATs……………………………………... 2 Monoamine Transporter Structure…………………………………………. 5 The Substrate Binding Pocket……………………………………… 10 The S1 binding site in LeuT………………………………... 11 The S1 binding site in MATs………………………………. 13 The S2 binding site in the extracellular vestibule………….. 14 Ion Binding Sites in MATs………………………………………… 17 The Na+ binding sites……………………………………….
    [Show full text]
  • Activity 2 the Brain and Drugs ______
    Activity 2 The Brain and Drugs ____________________________________________________________________________________ Core Concept: Addictive drugs affect signaling at the synapses in the reward pathway of the brain. Class time required: Approximately 40-60 minutes Teacher Provides: For each student • Copy of student handout entitled “The Brain and Drugs.” • Copies of note sheet for “Crossing the Divide: How Neurons Talk to Each Other * ” *Created by Lisa Brosnick, North Collins High School, North Collins, NY For each team: • Color copies of Sending Neuron diagrams that are enlarged to print on 11” X 17” or larger paper. Considering laminating this for use with multiple classes. • Color copies of Sending Neuron that are enlarged to print on 11” X 17” or larger paper. Considering laminating this for use with multiple classes. • A bag containing: o 10 tri-beads (Purchase at a craft store. These should be a single color.) o 2 Impulse cut-outs. o One set of label cards. Consider laminating these for use with multiple classes. • Access to computers with Internet (as a class or small groups of students) for viewing Crossing the Divide: How Neurons Talk to Each Other http://learn.genetics.utah.edu/content/addiction/reward/neurontalk.html This project was generously funded by Science Education Drug Abuse Partnership Award R25DA021697 from the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health. Life Sciences Learning Center 1 Copyright © 2010, University of Rochester May be copied for classroom use Suggested Class Procedure: 1.
    [Show full text]
  • Dopamine Uptake Through the Norepinephrine Transporter in Brain Regions with Low Levels of the Dopamine Transporter: Evidence from Knock-Out Mouse Lines
    The Journal of Neuroscience, January 15, 2002, 22(2):389–395 Dopamine Uptake through the Norepinephrine Transporter in Brain Regions with Low Levels of the Dopamine Transporter: Evidence from Knock-Out Mouse Lines Jose´ A. Moro´ n, Alicia Brockington, Roy A. Wise, Beatriz A. Rocha, and Bruce T. Hope Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224 Selective blockers of the norepinephrine transporter (NET) in- 20% in caudate and nucleus accumbens synaptosomes from hibit dopamine uptake in the prefrontal cortex. This suggests wild-type and DAT knock-out mice but had no effect in those that dopamine in this region is normally cleared by the some- from NET knock-out mice. Cocaine failed to block dopamine what promiscuous NET. We have tested this hypothesis by uptake into caudate or nucleus accumbens synaptosomes comparing the effects of inhibitors selective for the three mono- from DAT knock-out mice. Cocaine and GBR12909 each inhib- amine transporters with those of a nonspecific inhibitor, co- ited dopamine uptake into caudate synaptosomes from NET caine, on uptake of 3H-dopamine into synaptosomes from knock-out mice, but cocaine effectiveness was reduced in the frontal cortex, caudate nucleus, and nucleus accumbens from case of nucleus accumbens synaptosomes. Thus, whereas wild-type, NET, and dopamine transporter (DAT) knock-out dopamine uptake in caudate and nucleus accumbens depends mice. Dopamine uptake was inhibited by cocaine and niso- primarily on the DAT, dopamine uptake in frontal cortex de- xetine, but not by GBR12909, in frontal cortex synaptosomes pends primarily on the NET.
    [Show full text]
  • Neurotransmitter Transporters
    Annu. Rev. Neurosci. 1993. 16:73-93 NEUROTRANSMITTER TRANSPORTERS: Recent Progress 1 Susan G. Amara Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland, Oregon 97201 Michael J. Kuhar Neurosciences Branch, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland KEY WORDS: neurotransmitter reuptake, synaptic signal termination, uptake INTRODUCTION It has been known for many years that neurons and glia can accumulate neurotransmitters by a sodium dependent cotransport process that is, in many respects, similar to systems present in most cells for concentrating metabolites. By cotransporting a solute with sodium, the energy stored in transmembrane electrochemical gradients can be used to drive the solute by MCGILL UNIVERSITY LIBRARIES on 02/24/13. For personal use only. Annu. Rev. Neurosci. 1993.16:73-93. Downloaded from www.annualreviews.org into the cell (reviewed in Kanner & Schuldiner 1987; Trendelenburg 1991). A special appreciation of the neurotransmitter cotransport systems has devcIoped from studies, which indicate the existence of multiple uptake systems, each relatively selective for a specific neurotransmitter. Table I presents a list of brain uptake systems that have been identified. These transport activities are localized within the synaptic membranes of neurons that use the same transmitter and are probably the most important mech­ anism for terminating synaptic transmission. Many of these transporters I The US government has the right to retain a nonexclusive, royalty-free license in and to any copyright covering this paper. 73 74 AMARA & KUHAR Table 1 Neurotransmitter (candidates) have high affinitytransport systems Dopamine GABA Norepinephrine Glycine Serotonin Taurine Glutamate Proline Aspartate Adenosine or reuptake systems have been implicated as important sites for drug action.
    [Show full text]
  • Resistant Depression
    NEWS & ANALYSIS BIOBUSINESS BRIEFS DEAL WATCH NR2B antagonist pursued for treatment- resistant depression Roche has entered into an agreement with compared with non-selective NMDA receptor Evotec to fund the Phase II clinical development antagonists in preclinical studies. The effects of a selective N-methyl-d-aspartate (NMDA) of other oral, brain-penetrant NMDA receptor antagonist, EVT 101, for patients with receptor antagonists that bind to the treatment-resistant depression. EVT 101 was NR2B receptor subunit (including TXT-0300, originally discovered by Roche and licensed to Traxion Therapeutics; and MK-0657, Merck) Evotec in 2003 for further development. Roche have also been investigated, not only for will also pay Evotec to conduct Phase I safety the treatment of depression, but also pain and tolerability studies for EVT 103, a next and cognitive disorders. However, no generation compound to EVT 101, and an developments have been reported recently. upfront fee of US$10 million for the option to Although it is not well understood why buy back rights to the entire EVT 100 family of NMDA receptor antagonists are effective compounds. The total potential deal value is against treatment-resistant depression, as more than $300 million. Mathew notes, “...the rapid onset of action It is estimated that over 120 million people of these compounds could result in a decrease suffer from depression and that about one-third in long-term morbidity,” and thus warrants of patients treated for major depressive further investigation. Holger Wigström, disorder (MDD) do not respond satisfactorily. Professor at the Institute of Neuroscience and In addition, current therapies, such as selective Physiology, Göteborg University, Germany, serotonin-reuptake inhibitors, typically take who is examining the effects of NMDA several weeks to exert their effects.
    [Show full text]
  • Act Dextroamphetamine Sr
    PRODUCT MONOGRAPH ACT DEXTROAMPHETAMINE SR Dextroamphetamine Sulphate Sustained Release Capsules 10 mg and 15 mg Sympathomimetic Teva Canada Limited Date of Revision: 30 Novopharm Court December 10, 2019 Toronto, Ontario Canada M1B 2K9 www.tevacanada.com Submission Control No: 233804 ACT DEXTROAMPHETAMINE SR Page 1 of 25 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION ..........................................................3 SUMMARY PRODUCT INFORMATION ........................................................................3 INDICATIONS AND CLINICAL USE ..............................................................................3 CONTRAINDICATIONS ...................................................................................................4 WARNINGS AND PRECAUTIONS ..................................................................................5 ADVERSE REACTIONS ..................................................................................................10 DRUG INTERACTIONS ..................................................................................................11 DOSAGE AND ADMINISTRATION ..............................................................................13 ACTION AND CLINICAL PHARMACOLOGY ............................................................16 STORAGE AND STABILITY ..........................................................................................17 DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................17 PART II: SCIENTIFIC INFORMATION ................................................................................18
    [Show full text]
  • Neurotransmitter Transporters: Fruitful Targets for CNS Drug Discovery L Iversen
    Molecular Psychiatry (2000) 5, 357–362 2000 Macmillan Publishers Ltd All rights reserved 1359-4184/00 $15.00 www.nature.com/mp MILLENNIUM ARTICLE Neurotransmitter transporters: fruitful targets for CNS drug discovery L Iversen Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK More than 20 members have been identified in the neurotransmitter transporter family. These include the cell surface re-uptake mechanisms for monoamine and amino acid neurotransmit- ters and vesicular transporter mechanisms involved in neurotransmitter storage. The norepi- nephrine and serotonin re-uptake transporters are key targets for antidepressant drugs. Clini- cally effective antidepressants include those with selectivity for either NE or serotonin uptake, and compounds with mixed actions. The dopamine transporter plays a key role in mediating the actions of cocaine and the amphetamines and in conferring selectivity on dopamine neuro- toxins. The only clinically used compound to come so far from research on amino acid trans- porters is the antiepileptic drug tiagabine, a GABA uptake inhibitor. Molecular Psychiatry (2000) 5, 357–362. Keywords: neurotransmitter transporters; vesicular transporters; antidepressants; serotonin; norepi- nephrine; dopamine; cocaine; amphetamines Introduction for some time unchanged. A key observation was that the uptake of 3H-noradrenaline into the heart was vir- The concept that neurotransmitters are inactivated by tually eliminated in animals in which the sympathetic uptake of the released chemical
    [Show full text]
  • The Glutamate Uptake Inhibitor L- Trans=Pyrrolidine=2,4=Dicarboxylate Depresses Excitatory Synaptic Transmission Via a Presynapt
    The Journal of Neuroscience, November 1994, 14(11): 6754-6762 The Glutamate Uptake Inhibitor L- Trans=pyrrolidine=2,4=dicarboxylate Depresses Excitatory Synaptic Transmission via a Presynaptic Mechanism in Cultured Hippocampal Neurons Reiko Maki,’ Michael B. Robinson,lJ and Marc A. Dichter1-2 ‘David Mahoney Institute of Neurological Sciences and *Departments of Neurology and Pharmacology, University of Pennsylvania, School of Medicine and The Graduate Hospital, and 3The Children’s Seashore House, Children’s Hospital of Philadelphia, and Departments of Pediatrics and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 Sodium-dependent high-affinity uptake of glutamate is Most previous studies on the involvement of reuptake in ex- thought to play a major role in the maintenance of very low citatory synaptic transmissionhave shown potentiated neuronal extracellular concentrations of excitatory amino acids (EAA), responsesto exogenous/yapplied glutamate (Lodge et al., 1979, and may modulate the actions of released transmitter at 1980; Johnston et al., 1980; Saweda et al., 1985; Brodin et al., G-protein-coupled receptors and extrasynaptic receptors 1988; Hestrin et al., 1990). However, the temporal and spatial that are activated over a longer distance and time course. characteristics of exogenousapplication of glutamate may be We have examined the effects of the recently developed very different from synaptically released transmitter. Ionto- uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-Wan+ phoretically applied transmitters are not localized to the syn- PDC) on monosynaptically evoked excitatory postsynaptic apse, exist in nonphysiologic concentrations, and affect both currents (EPSCs) in very-low-density cultures of hippocam- synaptic and extrasynaptic receptors, and are therefore more pal neurons.
    [Show full text]
  • Brain NMDA Receptors in Schizophrenia and Depression
    biomolecules Review Brain NMDA Receptors in Schizophrenia and Depression Albert Adell 1,2 1 Institute of Biomedicine and Biotechnology of Cantabria, IBBTEC (CSIC-University of Cantabria), Calle Albert Einstein 22 (PCTCAN), 39011 Santander, Spain; [email protected] or [email protected] 2 Biomedical Research Networking Center for Mental Health (CIBERSAM), 39011 Santander, Spain Received: 3 June 2020; Accepted: 21 June 2020; Published: 23 June 2020 Abstract: N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals and humans. However, ketamine has been recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage in both conditions is similar, and positive symptoms of schizophrenia appear before antidepressant effects emerge. Here, we describe the temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats, and postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Hence, blockade of NMDA receptors in depressive-like status can lead to amelioration or remission of symptoms, whereas healthy individuals develop psychotic symptoms and schizophrenia patients show an exacerbation of these symptoms after the administration of NMDA receptor antagonists. Keywords: NMDA; depression; schizophrenia; subunit; glutamate; GABA 1. Introduction The N-Methyl-D-aspartate (NMDA) receptor (NMDAR) is an ionotropic glutamate receptor that possesses unique characteristics. The flow of ions through the channel is blocked by Mg2+. Two different processes are necessary for activating NMDARs.
    [Show full text]
  • The Trace Amine-Associated Receptor 1 Inhibits a Hyperglutamatergic State
    The trace amine-associated receptor 1 inhibits a hyperglutamatergic state induced by dopamine deficiency Alexandra Alvarsson1, Tiberiu L Stan1, Nicoletta Schintu1, Banafsheh Kadkhodaei2, Mark J Millan4, Thomas Perlmann2,3, Per Svenningsson1 1Department of Clinical Neuroscience, Center for Molecular Medicine; 2Ludwig Institute for Cancer Research; 3Department of Cell and Molecular Biology; Karolinska Institutet, Stockholm, Sweden 4URDN, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, France CONCLUSIONS: • Dopamine dysfunction caused by genetic ablation of Nurr1 leads to a hyperglutamatergic state in striatum. • This hyperglutamatergic state was normalized by a therapeutically used D2 receptor agonist and by a selective TAAR1 agonist, acting via CB1 receptors. • We here identify a modulatory and potentially therapeutic role of TAAR1 on dysfunctional corticostriatal glutamate release. BACKGROUND: RESULTS: The trace amine-associated receptor 1 (TAAR1) is expressed in the monoaminergic Evoked corticostriatal glutamate release was enhanced under dopamine systems of the brain where it plays an important neuromodulatory role [1]. It has been deficiency and attenuated by activation of D2R and TAAR1 proposed to interact with the dopamine D2 receptor (D2R) and the dopamine transporter [1], and has been implicated in neuropathological disorders including schizophrenia, • Evoked glutamate concentrations were significantly increased depression and Parkinson’s disease (PD) [1]. PD is characterized by the progressive loss in the striatum of cNurr1 KO mice compared to WT mice. of dopaminergic neurons projecting from the substantia nigra pars compacta to the striatum, which results in altered dynamics of glutamate throughout the basal ganglia [2]. • The enhanced glutamate release in cNurr1 KO mice was This imbalance may accelerate neuronal degeneration due to excitotoxic processes, and inhibited by local administration of D2R agonist ropinirole provides a possible therapeutic target [2].
    [Show full text]