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Pharmacotherapy Through the Inhibition of Glycine Transporters: An Update on and Beyond Schizophrenia

Chapter

Abstract

The glycine reuptake inhibitor (GRI) bitopertin (also known as RG1678 or RO-4917838), invented by Hoffmann–La Roche, was poised to make an impact on the pharmacotherapy of schizophrenia, but hope was finally dashed by the disappointing outcomes of the recently completed multi-centre phase III clinical trials. Against this backdrop, this review aims to survey the rationale and potential of GRIs to treat neuropsychiatric conditions beyond schizophrenia. Indeed, although the development of bitopertin as an anti-schizophrenia drug has since been shelved, it is still being pursued by Roche as a potential adjunctive medication for the treatment of obsessive–compulsive disorder. Several lines of research have independently indicated that the pharmacological inhibition of glycine reuptake may be relevant to the treatment of diverse clinical conditions, including depression, anxiety disorders, alcohol dependence, epilepsy, and pain. In each case, the rationale emphasizes the physiological impact of glycine reuptake inhibition on either the inhibitory glycinergic neurotransmission or the excitatory n-methyl-d-aspartate receptor–dependent glutamatergic neurotransmission. None of the proposed clinical applications, however, can readily incorporate and integrate, a priori, both expected neuropharmacological effects of GRIs. The dual action of glycine in the nervous system may be the Achilles heel in precisely predicting the outcome of the systemic effects of GRIs, which may explain why none of these approaches has yet yielded any clinic-ready GRI drug. A better understanding at the circuitry level implicated in the respective disorders would be needed to overcome this roadblock to drug discovery.

Keywords

Glutamate Glycine transporter NMDA receptor Schizophrenia Addiction Pain Obsessive–compulsive disorder 

References

  1. 1.
    Eulenburg V, Armsen W, Betz H, Gomeza J. Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci. 2005;30(6):325–33.PubMedCrossRefGoogle Scholar
  2. 2.
    Harvey RJ, Topf M, Harvey K, Rees MI. The genetics of hyperekplexia: more than startle! Trends Genet. 2008;24(9):439–47.PubMedCrossRefGoogle Scholar
  3. 3.
    Danysz W, Parsons CG. Glycine and N-methyld-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev. 1998;50(4):597–664.PubMedGoogle Scholar
  4. 4.
    Singer P, Dubroqua S, Yee BK. Inhibition of glycine transporter 1: the yellow brick road to new schizophrenia therapy? Curr Pharm Des. 2015;21(26):3771–87.PubMedCrossRefGoogle Scholar
  5. 5.
    Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs. 2011;25(10):859–85.PubMedCrossRefGoogle Scholar
  6. 6.
    Bugarski-Kirola D, Iwata N, Sameljak S, et al. Efficacy and safety of adjunctive bitopertin versus placebo in patients with suboptimally controlled symptoms of schizophrenia treated with antipsychotics — results: from the SearchLyte clinical trial. Neuropsychopharmacology. 2014;39:S291–472, T121.Google Scholar
  7. 7.
    Bugarski-Kirola D, Arango C, Fleischhacker WW, Bressan R, Nasrallah H, Lawrie S, Blaettler T, Garibaldi G, Reid C, Marder SE. Efficacy and safety of adjunctive bitopertin versus placebo in subjects with persistent predominant negative symptoms of schizophrenia treated with antipsychotics — update from the SearchLyte programme. Schizophr Res. 2014;153(Suppl 1):29.Google Scholar
  8. 8.
    Bugarski-Kirola D, Fleischhacker WW, Blaettler T, Edgar CJ, Milosavljevic-Ristic S, Lamour F, Sun S, Kapur S. Efficacy and safety of adjunctive bitopertin (10 and 20 mg) versus placebo in subjects with sub-optimally controlled symptoms of schizophrenia treated with antipsychotics — results from the Phase III TwiLyte study. Int J Neuropsychopharmacol. 2014;17(Suppl 1):65.Google Scholar
  9. 9.
    Umbricht D, Yoo K, Youssef E, Dorflinger E, Martin-Facklam M, Bausch A, Arrowsmith R, Alberati D, Marder SR, Santarelli L, editors. Glycine transporter type 1 (GLYT1) inhibitor RG1678: positive results of the proof-of-concept study for the treatment of negative symptoms in schizophrenia. Neuropsychopharmacol. 2010;35:s320–1.Google Scholar
  10. 10.
    Umbricht D, Martin-Facklam M, Pizzagalli E, Youssef E, Yoo K, Doerflinger E, Bausch A, Arrowsmith R, Alberati D, Santarelli L. Glycine transporter type 1 (GLYT1) inhibition RG1678: results of the proof-of-concept study for the treatment of negative symptoms in schizophrenia. Schizophr Bull. 2011;37 Suppl 1:324.Google Scholar
  11. 11.
    Umbricht D, Alberati D, Martin-Facklam M, Borroni E, Youssef EA, Ostland M, Wallace TL, Knoflach F, Dorflinger E, Wettstein JG, Bausch A, Garibaldi G, Santarelli L. Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study. JAMA Psychiatry. 2014;71:637–46.PubMedCrossRefGoogle Scholar
  12. 12.
    Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology and therapy of schizophrenia. Pharmacol Biochem Behav. 2012;100(4):665–77.PubMedCrossRefGoogle Scholar
  13. 13.
    Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML. Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol. 2001;41:237–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Möhler H, Boison D, Singer P, Feldon J, Pauly-Evers M, Yee BK. Glycine transporter 1 as a potential therapeutic target for schizophrenia-related symptoms: evidence from genetically modified mouse models and pharmacological inhibition. Biochem Pharmacol. 2011;81(9):1065–77.PubMedCrossRefGoogle Scholar
  15. 15.
    Depoortere R, Dargazanli G, Estenne-Bouhtou G, Coste A, Lanneau C, Desvignes C, et al. Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology. 2005;30(11):1963–85.PubMedCrossRefGoogle Scholar
  16. 16.
    Boulay D, Pichat P, Dargazanli G, Estenne-Bouhtou G, Terranova JP, Rogacki N, et al. Characterization of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia. Pharmacol Biochem Behav. 2008;91(1):47–58.PubMedCrossRefGoogle Scholar
  17. 17.
    Huang CC, Wei IH, Huang CL, Chen KT, Tsai MH, Tsai P, et al. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol Psychiatry. 2013;74(10):734–41.PubMedCrossRefGoogle Scholar
  18. 18.
    Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, Kremer I. A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol. 2013;16(3):501–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA, Moskal JR. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology. 2013;38(5):729–42.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Dubroqua S, Singer P, Boison D, Feldon J, Möhler H, Yee BK. Impacts of forebrain neuronal glycine transporter 1 disruption in the senescent brain: evidence for age-dependent phenotypes in Pavlovian learning. Behav Neurosci. 2010;124(6):839–50.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Williams NR, Schatzberg AF. NMDA antagonist treatment of depression. Curr Opin Neurobiol. 2016;36:112–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21(3):169–84.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15(1):53–63.PubMedCrossRefGoogle Scholar
  24. 24.
    Goodman WK, Grice DE, Lapidus KA, Coffey BJ. Obsessive–compulsive disorder. Psychiatr Clin N Am. 2014;37(3):257–67.CrossRefGoogle Scholar
  25. 25.
    Markarian Y, Larson MJ, Aldea MA, Baldwin SA, Good D, Berkeljon A, Murphy TK, Storch EA, McKay D. Multiple pathways to functional impairment in obsessive–compulsive disorder. Clin Psychol Rev. 2010;30(1):78–88.PubMedCrossRefGoogle Scholar
  26. 26.
    Brander G, Vigil AP, Larsson H, Mataix-Cols D. Systematic review of environmental risk factors for obsessive–compulsive disorder: a proposed roadmap from association to causation. Neurosci Biobehav Rev. 2016;S0149-7634(15):30229–3.Google Scholar
  27. 27.
    Grant JE. Clinical practice: obsessive–compulsive disorder. N Engl J Med. 2014;371(7):646–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Decloedt EH, Stein DJ. Current trends in drug treatment of obsessive–compulsive disorder. Neuropsychiatr Dis Treat. 2010;6:233–42.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Komossa K, Depping AM, Meyer M, Kissling W, Leucht S. Second-generation antipsychotics for obsessive compulsive disorder. Cochrane Database Syst Rev. 2010;12:CD008141.Google Scholar
  30. 30.
    Veale D, Miles S, Smallcombe N, Ghezai H, Goldacre B, Hodsoll J. Atypical antipsychotic augmentation in SSRI treatment refractory obsessive–compulsive disorder: a systematic review and meta-analysis. BMC Psychiatry. 2014;14:317.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bloch MH, Landeros-Weisenberger A, Kelmendi B, Coric V, Bracken MB, Leckman JF. A systematic review: antipsychotic augmentation with treatment refractory obsessive–compulsive disorder. Mol Psychiatry. 2006;11(7):622–32.PubMedCrossRefGoogle Scholar
  32. 32.
    Beck JS. Cognitive behavior therapy: basics and beyond. 2nd ed. New York: The Guilford Press; 2011. p. 19–20.Google Scholar
  33. 33.
    Cybulska EM. Obsessive compulsive disorder, the brain and electroconvulsive therapy. Br J Hosp Med (Lond). 2006;67(2):77–81.CrossRefGoogle Scholar
  34. 34.
    Barlow DH, Durand VM. Essentials of abnormal psychology. Belmont: Thomson Wadsworth; 2006.Google Scholar
  35. 35.
    Hartmann CJ, Lujan JL, Chaturvedi A, Goodman WK, Okun MS, McIntyre CC, Haq IU. Tractography activation patterns in dorsolateral prefrontal cortex suggest better clinical responses in OCD DBS. Front Neurosci. 2016;9:519.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB. American psychiatric association. Practice guideline for the treatment of patients with obsessive–compulsive disorder. Am J Psychiatry. 2007;164(7 Suppl):5–53.PubMedGoogle Scholar
  37. 37.
    Ting JT, Feng G. Glutamatergic synaptic dysfunction and obsessive–compulsive disorder. Curr Chem Genomics. 2008;2:62–75.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Wu P-L, Lane H-Y, Tang H-S, Tsai GE. Glutamate theory in developing novel pharmacotherapies for obsessive compulsive disorder: focusing on N-methyl- D-aspartate signaling. Biomedicine. 2012;2:75–9.CrossRefGoogle Scholar
  39. 39.
    Grados MA, Specht MW, Sung HM, Fortune D. Glutamate drugs and pharmacogenetics of OCD: a pathway-based exploratory approach. Expert Opin Drug Discovery. 2013;8(12):1515–27.CrossRefGoogle Scholar
  40. 40.
    Pittenger C. Glutamate modulators in the treatment of obsessive–compulsive disorder. Psychiatr Ann. 2015;45(6):308–15.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Wu PL, Tang HS, Lane HY, Tsai CA, Tsai GE. Sarcosine therapy for obsessive compulsive disorder: a prospective, open-label study. J Clin Psychopharmacol. 2011;31(3):369–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Greenberg WM, Benedict MM, Doerfer J, Perrin M, Panek L, Cleveland WL, Javitt DC. Adjunctive glycine in the treatment of obsessive–compulsive disorder in adults. J Psychiatr Res. 2009;43(6):664–70.PubMedCrossRefGoogle Scholar
  43. 43.
    Cleveland WL, DeLaPaz RL, Fawwaz RA, Challop RS. High-dose glycine treatment of refractory obsessive–compulsive disorder and body dysmorphic disorder in a 5-year period. Neural Plast. 2009;2009:768398.PubMedCrossRefGoogle Scholar
  44. 44.
    Kushner MG, Kim SW, Donahue C, Thuras P, Adson D, Kotlyar M, McCabe J, Peterson J, Foa EB. D-cycloserine augmented exposure therapy for obsessive–compulsive disorder. Biol Psychiatry. 2007;62(8):835–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Wilhelm S, Buhlmann U, Tolin DF, Meunier SA, Pearlson GD, Reese HE, Cannistraro P, Jenike MA, Rauch SL. Augmentation of behavior therapy with D-cycloserine for obsessive–compulsive disorder. Am J Psychiatry. 2008;165(3):335–41.PubMedCrossRefGoogle Scholar
  46. 46.
    Storch EA, Murphy TK, Goodman WK, Geffken GR, Lewin AB, Henin A, Micco JA, Sprich S, Wilhelm S, Bengtson M, Geller DA. A preliminary study of D-cycloserine augmentation of cognitive-behavioral therapy in pediatric obsessive–compulsive disorder. Biol Psychiatry. 2010;68(11):1073–6.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Foa E, Franklin ME, Moser J. Context in the clinic: how well do cognitivebehavioral therapies and medications work in combination? Biol Psychiatry. 2002;52(10):987–97.PubMedCrossRefGoogle Scholar
  48. 48.
    Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61(11):1136–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Otto MW, Tolin DF, Simon NM, Pearlson GD, Basden S, Meunier SA, Hofmann SG, Eisenmenger K, Krystal JH, Pollack MH. Efficacy of D-cycloserine for enhancing response to cognitive–behavior therapy for panic disorder. Biol Psychiatry. 2010;67(4):365–70.PubMedCrossRefGoogle Scholar
  50. 50.
    Guastella AJ, Richardson R, Lovibond PF, Rapee RM, Gaston JE, Mitchell P, Dadds MR. A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Biol Psychiatry. 2008;63(6):544–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, Shiekh M, Otto MW. Augmentation of exposure therapy for social anxiety disorder with D-Cycloserine. Arch Gen Psychiatry. 2006;63(3):298–304.PubMedCrossRefGoogle Scholar
  52. 52.
    Nations KR, Smits JA, Tolin DF, Rothbaum BO, Hofmann SG, Tart CD, Lee A, Schipper J, Sjogren M, Xue D, Szegedi A, Otto MW. Evaluation of the glycine transporter inhibitor Org25935 as augmentation to cognitive–behavioral therapy for panic disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychol. 2012;73(5):647–53.Google Scholar
  53. 53.
    Komatsu H, Furuya Y, Sawada K, Asada T. Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups. Eur J Pharmacol. 2015;746:252–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Depoortère R, Dargazanli G, Estenne-Bouhtou G, Coste A, Lanneau C, Desvignes C, et al. Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology. 2005;30(11):1963–85.PubMedCrossRefGoogle Scholar
  55. 55.
    Shorvon SD. The epidemiology and treatment of chronic and refractory epilepsy. Epilepsia. 1996;37(Suppl. 2):S1–3.PubMedCrossRefGoogle Scholar
  56. 56.
    Ben-Ari Y. Seizures beget seizures: the quest for GABA as a key player. Crit Rev Neurobiol. 2006;18(1–2):135–44.PubMedCrossRefGoogle Scholar
  57. 57.
    Schuele SU, Luders HO. Intractable epilepsy: management and therapeutic alternatives. Lancet Neurol. 2008;7(6):514–24.PubMedCrossRefGoogle Scholar
  58. 58.
    Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientists, vol. 5. New York: Cold Spring Harbor; 2015.Google Scholar
  59. 59.
    Hirsch E, Schmitz B, Carreno M. Epilepsy, antiepileptic drugs (AEDs) and cognition. Acta Neurol Scand Suppl. 2003;180:23–32.PubMedCrossRefGoogle Scholar
  60. 60.
    Arif H, Buchsbaum R, Weintraub D, Pierro J, Resor Jr SR, Hirsch LJ. Patient-reported cognitive side effects of antiepileptic drugs: predictors and comparison of all commonly used antiepileptic drugs. Epilepsy Behav. 2009;1491:202–9.CrossRefGoogle Scholar
  61. 61.
    Loscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia. 2011;52(4):657–78.PubMedCrossRefGoogle Scholar
  62. 62.
    Kanner AM. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol. 2016;12(2):106–16.PubMedCrossRefGoogle Scholar
  63. 63.
    Lapin IP. Antagonism of L-glycine to seizures induced by L-kynurenine, quinolinic acid and strychnine in mice. Eur J Pharmacol. 1981;71(4):495–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Seiler N, Sarhan S. Synergistic anticonvulsant effects of a GABA agonist and glycine. Gen Pharmacol. 1984;15(4):367–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Halsey MJ, Little HJ, Wardley-Smith B. Systemically administered glycine protects against strychnine convulsions, but not the behavioural effects of high pressure, in mice. J Physiol. 1989;408:431–41.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Toth E, Lajtha A, Sarhan S, Seiler N. Anticonvulsant effects of some inhibitory neurotransmitter amino acids. Neurochem Res. 1983;8(3):291–302.PubMedCrossRefGoogle Scholar
  67. 67.
    Peterson SL. Glycine potentiates the anticonvulsant action of diazepam and phenobarbital in kindled amygdaloid seizures of rats. Neuropharmacology. 1986;25(12):1359–63.PubMedCrossRefGoogle Scholar
  68. 68.
    Peterson SL, Frye GD. Glycine potentiates diazepam anticonvulsant activity in electroshock seizures of rats: possible sites of interaction in the brainstem. Brain Res Bull. 1987;18(6):715–21.PubMedCrossRefGoogle Scholar
  69. 69.
    Kalinichev M, Starr KR, Teague S, Bradford AM, Porter RA, Herdon HJ. Glycine transporter 1 (GlyT1) inhibitors exhibit anticonvulsant properties in the rat maximal electroshock threshold (MEST) test. Brain Res. 2010;1331:105–13.PubMedCrossRefGoogle Scholar
  70. 70.
    Socała K, Nieoczym D, Rundfeldt C, Wlaź P. Effects of sarcosine, a glycine transporter type 1 inhibitor, in two mouse seizure models. Pharmacol Rep. 2010;62(2):392–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhao J, Tao H, Xian W, Cai Y, Cheng W, Yin M, Liang G, Li K, Cui L, Zhao B. A highly selective inhibitor of glycine transporter-1 elevates the threshold for maximal electroshock-induced tonic seizure in mice. Biol Pharm Bull. 2016;39(2):174–80.PubMedCrossRefGoogle Scholar
  72. 72.
    Shen HY, van Vliet EA, Bright KA, Hanthorn M, Lytle NK, Gorter J, Aronica E, Boison D. Glycine transporter 1 is a target for the treatment of epilepsy. Neuropharmacology. 2015;99:554–65.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Singer P, Feldon J, Yee BK. The glycine transporter 1 inhibitor SSR504734 enhances working memory performance in a continuous delayed alternation task in C57BL/6 mice. Psychopharmacology. 2009;202(1–3):371–84.PubMedCrossRefGoogle Scholar
  74. 74.
    Croucher MJ, Bradford HF. 7-Chlorokynurenic acid, a strychnine-insensitive glycine receptor antagonist, inhibits limbic seizure kindling. Neurosci Lett. 1990;118(1):29–32.PubMedCrossRefGoogle Scholar
  75. 75.
    Croucher MJ, Bradford HF. The influence of strychnine-insensitive glycine receptor agonists and antagonists on generalized seizure thresholds. Brain Res. 1991;543:91–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Peterson SL. Anticonvulsant drug potentiation by glycine in maximal electroshock seizures is mimicked by D-serine and antagonized by 7-chlorokynurenic acid. Eur J Pharmacol. 1991;199(3):341–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Brodie MJ, Sills GJ. Combining antiepileptic drugs — rational polytherapy? Seizure. 2011;20(5):369–75.PubMedCrossRefGoogle Scholar
  78. 78.
    So EL. What is known about the mechanisms underlying SUDEP? Epilepsia. 2008;49(suppl 9):93–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Richerson GB, Buchanan GF. The serotonin axis: shared mechanisms in seizures, depression, and SUDEP. Epilepsia. 2011;52(Suppl. 1):28–38.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Boison D. Cell and gene therapies for refractory epilepsy. Curr Neuropharmacol. 2007;5(2):115–25.PubMedCrossRefGoogle Scholar
  81. 81.
    Shetty AK, Hattiangady B. Concise review: prospects of stem cell therapy for temporal lobe epilepsy. Stem Cells. 2007;25:2396–407.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Soderpalm B, Ericson M. Neurocircuitry involved in the development of alcohol addiction: the dopamine system and its access points. Curr Top Behav Neurosci. 2013;13:127–61.PubMedCrossRefGoogle Scholar
  83. 83.
    Spanagel R, Vengeliene V. New pharmacological treatment strategies for relapse prevention. Curr Top Behav Neurosci. 2013;13:583–609.PubMedCrossRefGoogle Scholar
  84. 84.
    Lidö HH, Stomberg R, Fagerberg A, Ericson M, Soderpalm B. The glycine reuptake inhibitor org 25935 interacts with basal and ethanol-induced dopamine release in rat nucleus accumbens. Alcohol Clin Exp Res. 2009;33(7):1151–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Lidö HH, Ericson M, Marston H, Söderpalm B. A role for accumbal glycine receptors in modulation of dopamine release by the glycine transporter-1 inhibitor Org25935. Front Psychol. 2011;2:8.Google Scholar
  86. 86.
    Molander A, Lidö HH, Löf E, Ericson M, Söderpalm B. The glycine reuptake inhibitor Org25935 decreases ethanol intake and preference in male Wistar rats. Alcohol Alcohol. 2007;42(1):11–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Szegedi A, de Bejczy A, Nations KR, Ruwe F, Soderpalm B, Michelson D, Gold L. Evaluation of glycine transporter inhibitor Org 25935 for the prevention of relapse in alcohol-dependent patients: a multisite, randomized, double-blind, placebo-controlled trial. Neuropsychopharmacology. 2012;38:S314–446.CrossRefGoogle Scholar
  88. 88.
    Molander A, Lof E, Stomberg R, Ericson M, Soderpalm B. Involvement of accumbal glycine receptors in the regulation of voluntary ethanol intake in the rat. Alcohol Clin Exp Res. 2005;29(1):38–45.PubMedCrossRefGoogle Scholar
  89. 89.
    Spanagel R, Bartsch D, Brors B, Dahmen N, Deussing J, Eils R, et al. An integrated genome research network for studying the genetics of alcohol addiction. Addict Biol. 2010;15(4):369–79.PubMedCrossRefGoogle Scholar
  90. 90.
    Lidö HH, Marston H, Ericson M, Soderpalm B. The glycine reuptake inhibitor Org24598 and acamprosate reduce ethanol intake in the rat; tolerance development to acamprosate but not to Org24598. Addict Biol. 2012;17(5):897–907.PubMedCrossRefGoogle Scholar
  91. 91.
    Achat-Mendes C, Dhonnchadha BA, Platt DM, Kantak K, Spealman RD. Glycine transporter-1 inhibition preceding extinction training inhibits reacquisition of cocaine seeking. Neuropsychopharmacology. 2012;37(13):2837–45.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    NicDhonnchadha BA, Pinard E, Alberati D, Wettstein JG, Spealman RD, Kantak KM. Inhibiting glycine transporter-1 facilitates cocaine-cue extinction an attenuates reacquisition of cocaine-seeking behavior. Drug Alcohol Depend. 2012;122(1–2):119–26.CrossRefGoogle Scholar
  93. 93.
    Nong Y, Huang YQ, Ju W, Kalia LV, Ahmadian G, Wang YT, et al. Glycine binding primes NMDA receptor internalization. Nature. 2003;422(6929):302–7.PubMedCrossRefGoogle Scholar
  94. 94.
    Balu DT, Coyle JT. Glutamate receptor composition of the post-synaptic density is altered in genetic mouse models of NMDA receptor hypo- and hyperfunction. Brain Res. 2011;1392:1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Vengeliene V, Bachteler D, Danysz W, Spanagel R. The role of the NMDA receptor in alcohol relapse: a pharmacological mapping study using the alcohol deprivation effect. Neuropharmacology. 2005;48(6):822–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Gass JT, Olive MF. Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol. 2008;75(1):218–65.PubMedCrossRefGoogle Scholar
  97. 97.
    Sesack SR, Grace AA. Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacology. 2010;35(1):27–47.PubMedCrossRefGoogle Scholar
  98. 98.
    Dohi T, Morita K, Kitayama T, Motoyama N, Morioka N. Glycine transporter inhibitors as a novel drug discovery strategy for neuropathic pain. Pharmacol Ther. 2009;123(1):54–79.PubMedCrossRefGoogle Scholar
  99. 99.
    Tanabe M, Takasu K, Yamaguchi S, Kodama D, Ono H. Glycine transporter inhibitors as a potential therapeutic strategy for chronic pain with memory impairment. Anesthesiology. 2008;108(5):929–37.PubMedCrossRefGoogle Scholar
  100. 100.
    Morita K. Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. J Pharmacol ExpTher. 2008;326(2):633–45.CrossRefGoogle Scholar
  101. 101.
    Yoshikawa S, Oguchi T, Funahashi Y, de Groat WC, Yoshimura N. Glycine transporter type 2 (GlyT2) inhibitor ameliorates bladder overactivity and nociceptive behavior in rats. Eur Urol. 2012;62(4):704–12.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Cheng W, Yin Q, Cheng MY, Chen HS, Wang S, Feng T, Zeng YM, Liu GJ. Intracerebroventricular or intrathecal injection of glycine produces analgesia in thermal nociception and chemical nociception via glycine receptors. Eur J Pharmacol. 2009;614(1–3):44–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Hermanns H, Muth-Selbach U, Williams R, Krug S, Lipfert P, Werdehausen R, Braun S, Bauer I. Differential effects of spinally applied glycine transporter inhibitors on nociception in a rat model of neuropathic pain. Neurosci Lett. 2008;445(3):214–9.PubMedCrossRefGoogle Scholar
  104. 104.
    Haranishi Y, Hara K, Terada T, Nakamura S, Sata T. The antinociceptive effect of intrathecal administration of glycine transporter-2 inhibitor ALX1393 in a rat acute pain model. Anesth Analg. 2010;110(2):615–21.PubMedCrossRefGoogle Scholar
  105. 105.
    Nishikawa Y, Sasaki A, Kuraishi Y. Blockade of glycine transporter (GlyT) 2, but not GlyT1, ameliorates dynamic and static mechanical allodynia in mice with herpetic or postherpetic pain. J Pharmacol Sci. 2010;112(3):352–60.PubMedCrossRefGoogle Scholar
  106. 106.
    Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, Rauck RL, Backonja MM, Quessy SN, Meisner PD. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology. 2002;59(11):1694–700.PubMedCrossRefGoogle Scholar
  107. 107.
    Beyer C, Komisaruk BR, Lopez-Colome AM, Caba M. Administration of AP5, a glutamate antagonist, unmasks glycine analgesic actions in the rat. Pharmacol Biochem Behav. 1992;42(2):229–32.PubMedCrossRefGoogle Scholar
  108. 108.
    Centeno MV, Mutso A, Millecamps M, Apkarian AV. Prefrontal cortex and spinal cord mediated anti-neuropathy and analgesia induced by sarcosine, a glycine-T1 transporter inhibitor. Pain. 2009;145(1–2):176–83.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Kodama D, Ono H, Tanabe M. Increased hippocampal glycine uptake and cognitive dysfunction after peripheral nerve injury. Pain. 2011;152(4):809–17.PubMedCrossRefGoogle Scholar
  110. 110.
    Munts AG, van der Plas AA, Voormolen JH, Marinus J, Teepe-Twiss IM, Onkenhout W, van Gerven JM, van Hilten JJ. Intrathecal glycine for pain and dystonia in complex regional pain syndrome. Pain. 2009;146(1–2):199–204.PubMedCrossRefGoogle Scholar
  111. 111.
    Kantrowitz JT, Woods SW, Petkova E, Cornblatt B, Corcoran CM, Chen H, Silipo G, Javitt DC. D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial. Lancet Psychiatry. 2015;2(5):403–12.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Roche Diagnostics International Ltd.RotkreuzSwitzerland
  2. 2.Department of Rehabilitation SciencesThe Hong Kong Polytechnic UniversityHung HomHong Kong

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