Generic placeholder image

Current Psychiatry Research and Reviews

Author(s): Marcell Harhai and Laszlo G. Harsing*

DOI: 10.2174/2666082218666220126111415

DownloadDownload PDF Flyer Cite As
An Overview of Glycine Transporter Subtype 1 Inhibitors Under Preclinical and Clinical Evaluation for the Treatment of Alcohol Abuse

Page: [17 - 35] Pages: 19

  • * (Excluding Mailing and Handling)

Abstract

Being a historical issue that withstands multiple societal control measures, alcohol abuse remains a major healthcare problem. Despite worldwide efforts to limit consumption and educate people about its effects, consumption rates remain unchanged. Alcohol abuse arises from chronic alcohol exposure-caused permanent synaptic plasticity changes in the brain. These manifest in life-threatening withdrawal symptoms and drive relapse even after detoxification and treatment. Since ethanol has multiple targets in the human brain, it warrants a multiapproach therapy; here, we introduce the potential therapeutic effects of glycine transporter subtype 1 inhibitors. We have listed the various glycine transporter 1 inhibitors used in studies of alcoholism and how they influenced glycine release from rat hippocampus was demonstrated in a preliminary study. Glycine transporters modulate both glutamatergic and glycinergic pathways: (i) glutamatergic neurotransmission plays an important role in the development of chronic changes in alcoholism as daily alcohol administration was shown to increase N-methyl-D-aspartic acid receptor activity long-term, and (ii) ethanol has access to the dopaminergic reward system via glycine receptors, being an allosteric modulator of glycine receptors. This manuscript summarises the progress and development of glycine transporter 1 inhibitors, characterizing them by their mode of action adverse effects, and discusses their clinical applicability. Furthermore, we highlight the progress in the latest clinical trials, outline currently applied treatment methods, and offer suggestions for implementing glycine transporter 1 inhibitors into the long-term treatment of alcohol abuse.

Keywords: GlyT1 inhibitors, NMDA receptors, glycine, alcohol abuse, reward system in alcoholism, treatment of alcoholism, HIV/AIDS.

Graphical Abstract

[1]
Keller M. A historical overview of alcohol and alcoholism. Cancer Res 1979; 39(7 Pt 2): 2822-9.
[PMID: 376124]
[2]
WHO Global status report on alcohol and health 2011. Vol. 122. Available from: http://www.who. int/substance_abuse/publications/global_alcohol_report/msbgsruprofiles.pdf
[3]
Harsing LGJ. An overview on GlyT-1 inhibitors under evaluation for the treatment of schizophrenia. Drugs Future 2013; 38(8): 555-68.
[4]
Harvey RJ, Yee BK. Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov 2013; 12(11): 866-85.
[http://dx.doi.org/10.1038/nrd3893] [PMID: 24172334]
[5]
Lynch JW. Molecular structure and function of the glycine receptor chloride channel. Physiol Rev 2004; 84(4): 1051-95.
[http://dx.doi.org/10.1152/physrev.00042.2003] [PMID: 15383648]
[6]
Waxham MN. Neurotransmitter ReceptorsFrom Molecules to Networks. Amsterdam, Netherland: Elsevier 2004; pp. 299-334. Available from: https://www.sciencedirect.com/topics/neuroscience/glycine-receptor
[http://dx.doi.org/10.1016/B978-012148660-0/50012-3]
[7]
Briggs CA, Gopalakrishnan M, Laboratories A, Park A. 2. 22 Ion Channels – Ligand Gated. In: Taylor JB, Trigge DJ, EdsComprehensive Medical Chemistry II. Amsterdam, Netherland: Elsevier Ltd 2007; pp. 877-918.
[8]
Chen NH, Reith MEA, Quick MW. Synaptic uptake and beyond: The sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch 2004; 447(5): 519-31.
[http://dx.doi.org/10.1007/s00424-003-1064-5] [PMID: 12719981]
[9]
Gether U, Andersen PH, Larsson OM, Schousboe A. Neurotransmitter transporters: Molecular function of important drug targets. Trends Pharmacol Sci 2006; 27(7): 375-83.
[http://dx.doi.org/10.1016/j.tips.2006.05.003] [PMID: 16762425]
[10]
Harsing LG, Zsilla G, Matyus P, et al. Interactions between glycine transporter type 1 (GlyT-1) and some inhibitor mole-cules - glycine transporter type 1 and its inhibitors. (review) Acta Physiol Hung 2012; 99(1): 1-17.
[http://dx.doi.org/10.1556/APhysiol.99.2012.1.1] [PMID: 22425803]
[11]
Roux MJ, Supplisson S. Neuronal and glial glycine transporters have different stoichiometries. Neuron 2000; 25(2): 373-83.
[http://dx.doi.org/10.1016/S0896-6273(00)80901-0] [PMID: 10719892]
[12]
Betz H, Gomeza J, Armsen W, Scholze P, Eulenburg V. Glycine Transporters: Essential Regulators of Synaptic Trans-mission. Biochem Soc Trans 2006; 34(Pt. 1): 55-8.
[13]
Harsing LG Jr, Matyus P. Mechanisms of glycine release, which build up synaptic and extrasynaptic glycine levels: The role of synaptic and non-synaptic glycine transporters. Brain Res Bull 2013; 93: 110-9.
[http://dx.doi.org/10.1016/j.brainresbull.2012.12.002] [PMID: 23266673]
[14]
Vandenberg RJ, Shaddick K, Ju P. Molecular basis for substrate discrimination by glycine transporters. J Biol Chem 2007; 282(19): 14447-53.
[http://dx.doi.org/10.1074/jbc.M609158200] [PMID: 17383967]
[15]
Kalbaugh TL, Zhang J, Diamond JS. Coagonist release modulates NMDA receptor subtype contributions at synaptic inputs to retinal ganglion cells. J Neurosci 2009; 29(5): 1469-79.
[http://dx.doi.org/10.1523/JNEUROSCI.4240-08.2009] [PMID: 19193893]
[16]
Papp A, Juranyi Z, Nagymajtenyi L, Matyus P, Harsing LG Jr. The synaptic and nonsynaptic glycine transporter type-1 inhibitors Org-24461 and NFPS alter single neuron firing rate in the rat dorsal raphe nucleus. Further evidence for a glu-tamatergic-serotonergic interaction and its role in antipsychotic action. Neurochem Int 2008; 52(1-2): 130-4.
[http://dx.doi.org/10.1016/j.neuint.2007.06.030] [PMID: 17669555]
[17]
Harsing LG Jr, Juranyi Z, Gacsalyi I, Tapolcsanyi P, Czompa A, Matyus P. Glycine transporter type-1 and its inhibitors. Curr Med Chem 2006; 13(9): 1017-44.
[http://dx.doi.org/10.2174/092986706776360932] [PMID: 16611082]
[18]
Nagy K, Marko B, Zsilla G, et al. Alterations in brain extracellular dopamine and glycine levels following combined ad-ministration of the glycine transporter type-1 inhibitor Org-24461 and risperidone. Neurochem Res 2010; 35(12): 2096-106.
[http://dx.doi.org/10.1007/s11064-010-0241-0] [PMID: 20725779]
[19]
Atkinson BN, Bell SC, De Vivo M, et al. ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol 2001; 60(6): 1414-20.
[http://dx.doi.org/10.1124/mol.60.6.1414] [PMID: 11723250]
[20]
Ágoston M, Rónai É, Szabó É, Kiricsi P, Hársing LG, Szénási G. The Possible Mechanism of Respiratory Depression Caused by the Selective Glycine Transporter-1 Inhibitor NFPS. 41st European Brain and Behaviour Society Meeting. 2009 Sep 13-18; Rhodes Island, Greece.
[21]
Cioffi CL, Guzzo PR. Inhibitors of glycine transporter-1: Potential therapeutics for the treatment of CNS disorders. Curr Top Med Chem 2016; 16(29): 3404-37.
[http://dx.doi.org/10.2174/1568026616666160405113340] [PMID: 27048272]
[22]
Alberati-Giani D, Ceccarelli Simona M, Pinard E, Stalder H. Piperidine-benzenesulfonamide derivatives. CA2515838A1 2004.
[23]
Brown A, Carlyle I, Clark J, et al. Discovery and SAR of org 24598-a selective glycine uptake inhibitor. Bioorg Med Chem Lett 2001; 11(15): 2007-9.
[http://dx.doi.org/10.1016/S0960-894X(01)00355-9] [PMID: 11454468]
[24]
Mezler M, Hornberger W, Mueller R, et al. Inhibitors of GlyT1 affect glycine transport via discrete binding sites. Mol Pharmacol 2008; 74(6): 1705-15.
[http://dx.doi.org/10.1124/mol.108.049312] [PMID: 18815213]
[25]
Aubrey KR, Vandenberg RJN. N[3-(4;-fluorophenyl)-3-(4;-phenylphenoxy)propyl]sarcosine (NFPS) is a selective persis-tent inhibitor of glycine transport. Br J Pharmacol 2001; 134(7): 1429-36.
[http://dx.doi.org/10.1038/sj.bjp.0704381] [PMID: 11724748]
[26]
Kopec K, Flood DG, Gasior M, et al. Glycine transporter (GlyT1) inhibitors with reduced residence time increase prepulse inhibition without inducing hyperlocomotion in DBA/2 mice. Biochem Pharmacol 2010; 80(9): 1407-17.
[http://dx.doi.org/10.1016/j.bcp.2010.07.004] [PMID: 20637735]
[27]
Gomeza J, Hülsmann S, Ohno K, et al. Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in glycinergic inhibition. Neuron 2003; 40(4): 785-96.
[http://dx.doi.org/10.1016/S0896-6273(03)00672-X] [PMID: 14622582]
[28]
Szoke K, Härtel K, Grass D, Hirrlinger PG, Hirrlinger J, Hülsmann S. Glycine transporter 1 expression in the ventral res-piratory group is restricted to protoplasmic astrocytes. Brain Res 2006; 1119(1): 182-9.
[http://dx.doi.org/10.1016/j.brainres.2006.08.089] [PMID: 17010320]
[29]
Perry KW, Falcone JF, Fell MJ, et al. Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas. Neuropharmacology 2008; 55(5): 743-54.
[http://dx.doi.org/10.1016/j.neuropharm.2008.06.016] [PMID: 18602930]
[30]
Yang CR, Svensson KA. Allosteric modulation of NMDA receptor via elevation of brain glycine and D-serine: The ther-apeutic potentials for schizophrenia. Pharmacol Ther 2008; 120(3): 317-32.
[http://dx.doi.org/10.1016/j.pharmthera.2008.08.004] [PMID: 18805436]
[31]
Conn PJ, Tamminga C, Schoepp DD, Lindsley C. Schizophrenia: Moving beyond monoamine antagonists. Mol Interv 2008; 8(2): 99-107.
[http://dx.doi.org/10.1124/mi.8.2.7] [PMID: 18403654]
[32]
Porter RA, Dawson LA. GlyT-1 inhibitors: From hits to clinical candidates. In: Celanire S, Poli S, Eds.Small Molecule Therapeutics for Schizophrenia Topics in Medicinal Chemistry. 2015.
[33]
Arias-Carrión O, Stamelou M, Murillo-Rodríguez E, Menéndez-González M, Pöppel E. Dopaminergic reward system: A short integrative review. Int Arch Med 2010; 3(1): 24.
[http://dx.doi.org/10.1186/1755-7682-3-24] [PMID: 20925949]
[34]
Schultz W. Behavioral dopamine signals. Trends Neurosci 2007; 30(5): 203-10.
[http://dx.doi.org/10.1016/j.tins.2007.03.007] [PMID: 17400301]
[35]
Lüscher C. Drugs of AbuseBasic & Clinical Pharmacology. 13th ed. New York, USA: McGraw-Hill Education 2013; pp. 552-66.
[36]
Lüscher C, Malenka RC. Drug-evoked synaptic plasticity in addiction: From molecular changes to circuit remodeling. Neuron 2011; 69(4): 650-63.
[http://dx.doi.org/10.1016/j.neuron.2011.01.017] [PMID: 21338877]
[37]
Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 1988; 85(14): 5274-8.
[http://dx.doi.org/10.1073/pnas.85.14.5274] [PMID: 2899326]
[38]
Nestler EJ. Is there a common molecular pathway for addiction? Nat Neurosci 2005; 8(11): 1445-9.
[http://dx.doi.org/10.1038/nn1578] [PMID: 16251986]
[39]
Kauer JA, Malenka RC. Synaptic plasticity and addiction. Nat Rev Neurosci 2007; 8(11): 844-58.
[http://dx.doi.org/10.1038/nrn2234] [PMID: 17948030]
[40]
Heinz A, Löber S, Georgi A, et al. Reward craving and withdrawal relief craving: Assessment of different motivational pathways to alcohol intake. Alcohol Alcohol 2003; 38(1): 35-9.
[http://dx.doi.org/10.1093/alcalc/agg005] [PMID: 12554605]
[41]
Ji D, Gilpin NW, Richardson HN, Rivier CL, Koob GF. Effects of naltrexone, duloxetine, and a corticotropin-releasing factor type 1 receptor antagonist on binge-like alcohol drinking in rats. Behav Pharmacol 2008; 19(1): 1-12.
[http://dx.doi.org/10.1097/FBP.0b013e3282f3cf70] [PMID: 18195589]
[42]
Banerjee N. Neurotransmitters in alcoholism: A review of neurobiological and genetic studies. Indian J Hum Genet 2014; 20(1): 20-31.
[http://dx.doi.org/10.4103/0971-6866.132750] [PMID: 24959010]
[43]
Tsai G, Gastfriend DR, Coyle JT. The glutamatergic basis of human alcoholism. Am J Psychiatry 1995; 152(3): 332-40.
[http://dx.doi.org/10.1176/ajp.152.3.332] [PMID: 7864257]
[44]
Krystal JH, Staley J, Mason G, et al. γ-Aminobutyric acid type A receptors and alcoholism: Intoxication, dependence, vulnerability, and treatment Arch Gen Psychiatry 2006; 63(9): 957-68.
[http://dx.doi.org/10.1001/archpsyc.63.9.957] [PMID: 16952998]
[45]
Verheul R, Van Den Brink W, Geerlings P. A Three-pathway psychobiological model of craving for alcohol. Alcohol Alcohol 1999; 34(2): 197-222.
[http://dx.doi.org/10.1093/alcalc/34.2.197]
[46]
Heinz A, Beck A, Grüsser SM, Grace AA, Wrase J. Identifying the neural circuitry of alcohol craving and relapse vulner-ability. Addict Biol 2009; 14(1): 108-18.
[http://dx.doi.org/10.1111/j.1369-1600.2008.00136.x] [PMID: 18855799]
[47]
Weiss F, Lorang MT, Bloom FE, Koob GF. Oral alcohol self-administration stimulates dopamine release in the rat nu-cleus accumbens: Genetic and motivational determinants. J Pharmacol Exp Ther 1993; 267(1): 250-8.
[PMID: 8229752]
[48]
Rassnick S, Pulvirenti L, Koob GF. Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens. Psychopharmacology (Berl) 1992; 109(1-2): 92-8.
[http://dx.doi.org/10.1007/BF02245485] [PMID: 1365677]
[49]
Volkow ND, Wang GJ, Telang F, et al. Profound decreases in dopamine release in striatum in detoxified alcoholics: Pos-sible orbitofrontal involvement. J Neurosci 2007; 27(46): 12700-6.
[http://dx.doi.org/10.1523/JNEUROSCI.3371-07.2007] [PMID: 18003850]
[50]
Rassnick S, Stinus L, Koob GF. The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the meso-limbic dopamine system on oral self-administration of ethanol in the rat. Brain Res 1993; 623(1): 16-24.
[http://dx.doi.org/10.1016/0006-8993(93)90004-7] [PMID: 8221085]
[51]
Molander A, Söderpalm B. Accumbal strychnine-sensitive glycine receptors: An access point for ethanol to the brain reward system. Alcohol Clin Exp Res 2005; 29(1): 27-37.
[http://dx.doi.org/10.1097/01.ALC.0000150012.09608.81] [PMID: 15654288]
[52]
Mihic SJ, Ye Q, Wick MJ, et al. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature 1997; 389(6649): 385-9.
[http://dx.doi.org/10.1038/38738] [PMID: 9311780]
[53]
Gilpin NW, Koob GF. Neurobiology of alcohol dependence: Focus on motivational mechanisms. Alcohol Res Health 2008; 31(3): 185-95.
[54]
Colombo G, Grant KA. NMDA receptor complex antagonists have ethanol-like discriminative stimulus effects. Ann N Y Acad Sci 1992; 654(1): 421-3.
[http://dx.doi.org/10.1111/j.1749-6632.1992.tb25986.x] [PMID: 1385933]
[55]
Carboni S, Isola R, Gessa GL, Rossetti ZL. Ethanol prevents the glutamate release induced by N-methyl-D-aspartate in the rat striatum. Neurosci Lett 1993; 152(1-2): 133-6.
[http://dx.doi.org/10.1016/0304-3940(93)90501-B] [PMID: 8100051]
[56]
Roberto M, Schweitzer P, Madamba SG, Stouffer DG, Parsons LH, Siggins GR. Acute and chronic ethanol alter glu-tamatergic transmission in rat central amygdala: An in vitro and in vivo analysis. J Neurosci 2004; 24(7): 1594-603.
[http://dx.doi.org/10.1523/JNEUROSCI.5077-03.2004] [PMID: 14973247]
[57]
Pulvirenti L, Diana M. Drug dependence as a disorder of neural plasticity: Focus on dopamine and glutamate. Rev Neurosci 2001; 12(2): 141-58.
[http://dx.doi.org/10.1515/REVNEURO.2001.12.2.141] [PMID: 11392455]
[58]
Littleton JM. Acamprosate in alcohol dependence: Implications of a unique mechanism of action. J Addict Med 2007; 1(3): 115-25.
[http://dx.doi.org/10.1097/ADM.0b013e318156c26f] [PMID: 21768946]
[59]
Pál B. Involvement of extrasynaptic glutamate in physiological and pathophysiological changes of neuronal excitabil-ity. Cell Mol Life Sci 2018; 75(16): 2917-49.
[http://dx.doi.org/10.1007/s00018-018-2837-5] [PMID: 29766217]
[60]
Papouin T, Oliet SHR. Organization, control and function of extrasynaptic NMDA receptors. Philos Trans R Soc Lond B Biol Sci 2014; 369(1654): 20130601.
[http://dx.doi.org/10.1098/rstb.2013.0601] [PMID: 25225095]
[61]
Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 2013; 14(6): 383-400.
[http://dx.doi.org/10.1038/nrn3504] [PMID: 23686171]
[62]
Le Meur K, Galante M, Angulo MC, Audinat E. Tonic activation of NMDA receptors by ambient glutamate of non-synaptic origin in the rat hippocampus. J Physiol 2007; 580(Pt. 2): 373-83.
[http://dx.doi.org/10.1113/jphysiol.2006.123570] [PMID: 17185337]
[63]
Kollen M, Dutar P, Jouvenceau A. The magnitude of hippocampal long term depression depends on the synaptic loca-tion of activated NR2-containing N-methyl-D-aspartate receptors. Neuroscience 2008; 154(4): 1308-17.
[http://dx.doi.org/10.1016/j.neuroscience.2008.04.045] [PMID: 18538939]
[64]
Liu D dan, Yang Q, Li S tian. Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neu-rons. Vol. 93. Brain Res Bull 2013; 93: 10-6.
[65]
Yang Q, Zhu G, Liu D, et al. Extrasynaptic NMDA receptor dependent long-term potentiation of hippocampal CA1 pyramidal neurons. Sci Rep 2017; 7(1): 3045.
[http://dx.doi.org/10.1038/s41598-017-03287-7] [PMID: 28596523]
[66]
Papouin T, Ladépêche L, Ruel J, et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 2012; 150(3): 633-46.
[http://dx.doi.org/10.1016/j.cell.2012.06.029] [PMID: 22863013]
[67]
Rusakov DA, Scimemi A, Walker MC, Kullmann DM. Comment on “Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity”. Science 2004; 305(5692): 1912.
[http://dx.doi.org/10.1126/science.1101128] [PMID: 15448254]
[68]
Ahmadi S, Muth-Selbach U, Lauterbach A, Lipfert P, Neuhuber WL, Zeilhofert HU. Facilitation of spinal NMDA recep-tor currents by spillover of synaptically released glycine. Science 2003; 300(5628): 2094-7.
[http://dx.doi.org/10.1126/science.1083970]
[69]
Horio M, Kohno M, Fujita Y, et al. Levels of D-serine in the brain and peripheral organs of serine racemase (Srr) knock-out mice. Neurochem Int 2011; 59(6): 853-9.
[http://dx.doi.org/10.1016/j.neuint.2011.08.017] [PMID: 21906644]
[70]
Yamamoto S, Morinobu S, Iwamoto Y, et al. Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder. J Psychiatr Res 2010; 44(15): 1069-74.
[http://dx.doi.org/10.1016/j.jpsychires.2010.03.013] [PMID: 20427053]
[71]
Holecek M, Kovarik M. Alterations in protein metabolism and amino acid concentrations in rats fed by a high-protein (casein-enriched) diet - effect of starvation. Food Chem Toxicol 2011; 49(12): 3336-42.
[http://dx.doi.org/10.1016/j.fct.2011.09.016] [PMID: 21963952]
[72]
Zafra F, Aragon C, Olivares L, Danbolt NC, Giménez C, Storm-Mathisen J. Glycine transporters are differentially expressed among CNS cells. J Neurosci 1995; 15(5 II): 3952-69.
[73]
Okamoto M, Akanuma S, Tachikawa M, Hosoya K. Characteristics of glycine transport across the inner blood-retinal barrier. Neurochem Int 2009; 55(8): 789-95.
[http://dx.doi.org/10.1016/j.neuint.2009.08.001] [PMID: 19666071]
[74]
Harsing LG Jr, Szénási G, Zelles T, Köles L. Purinergic-glycinergic interaction in neurodegenerative and neuroinflamma-tory disorders of the retina. Int J Mol Sci 2021; 22(12): 6209.
[http://dx.doi.org/10.3390/ijms22126209] [PMID: 34201404]
[75]
Sakata K, Sato K, Schloss P, Betz H, Shimada S, Tohyama M. Characterization of glycine release mediated by glycine transporter 1 stably expressed in HEK-293 cells. Brain Res Mol Brain Res 1997; 49(1-2): 89-94.
[http://dx.doi.org/10.1016/S0169-328X(97)00126-5] [PMID: 9387867]
[76]
Zhang HX, Hyrc K, Thio LL. The glycine transport inhibitor sarcosine is an NMDA receptor co-agonist that differs from glycine. J Physiol 2009; 587(Pt 13): 3207-20.
[http://dx.doi.org/10.1113/jphysiol.2009.168757] [PMID: 19433577]
[77]
Wang J, Lanfranco MF, Gibb SL, Yowell QV, Carnicella S, Ron D. Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse. J Neurosci 2010; 30(30): 10187-98.
[http://dx.doi.org/10.1523/JNEUROSCI.2268-10.2010] [PMID: 20668202]
[78]
Perkins DI, Trudell JR, Crawford DK, Alkana RL, Davies DL. Targets for ethanol action and antagonism in loop 2 of the extracellular domain of glycine receptors. J Neurochem 2008; 106(3): 1337-49.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05476.x] [PMID: 18485105]
[79]
Söderpalm B, Löf E, Ericson M. Mechanistic studies of ethanol’s interaction with the mesolimbic dopamine reward sys-tem. Pharmacopsychiatry 2009; 42(Suppl. 1): S87-94.
[http://dx.doi.org/10.1055/s-0029-1220690]
[80]
Lidö HH, Ericson M, Marston H, Söderpalm B. A role for accumbal glycine receptors in modulation of dopamine re-lease by the glycine transporter-1 inhibitor org25935. Front Psychiatry 2011; 2(MAR): 8.
[http://dx.doi.org/10.3389/fpsyt.2011.00008] [PMID: 21556278]
[81]
Koller G, Zill P, Fehr C, et al. No association of alcohol dependence with SLC6A5 and SLC6A9 glycine transporter pol-ymorphisms. Addict Biol 2009; 14(4): 506-8.
[82]
Molander A, Lidö HH, Löf E, Ericson M, Söderpalm B. The glycine reuptake inhibitor Org 25935 decreases ethanol intake and preference in male wistar rats. Alcohol Alcohol 2007; 42(1): 11-8.
[http://dx.doi.org/10.1093/alcalc/agl085] [PMID: 17098748]
[83]
Lidö HH, Jonsson S, Hyytiä P, Ericson M, Söderpalm B. Further characterization of the GlyT-1 inhibitor Org25935: anti-alcohol, neurobehavioral, and gene expression effects. J Neural Transm (Vienna) 2017; 124(5): 607-19.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399095/ [Internet].
[http://dx.doi.org/10.1007/s00702-017-1685-z] [PMID: 28161754]
[84]
Lindsley C. GlyT1 - Up from the Ashes. The importance of not condemning a mechanism based on a single chemotype. ACS Chem Neurosci 2010; 1(3): 165-6.
[http://dx.doi.org/10.1021/cn100017a] [PMID: 22778822]
[85]
Lidö HH, Stomberg R, Fagerberg A, Ericson M, Söderpalm 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.
[http://dx.doi.org/10.1111/j.1530-0277.2009.00938.x] [PMID: 19389199]
[86]
Vengeliene V, Leonardi-Essmann F, Sommer WH, Marston HM, Spanagel R. Glycine transporter-1 blockade leads to persistently reduced relapse-like alcohol drinking in rats. Biol Psychiatry 2010; 68(8): 704-11.
[http://dx.doi.org/10.1016/j.biopsych.2010.05.029] [PMID: 20655511]
[87]
Wee S, Koob GF. The role of the dynorphin-κ opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology (Berl) 2010; 210(2): 121-35.
[http://dx.doi.org/10.1007/s00213-010-1825-8] [PMID: 20352414]
[88]
Spanagel R, Vengeliene V. New pharmacological treatment strategies for relapse prevention. Curr Top Behav Neurosci 2013; 13: 583-609.
[http://dx.doi.org/10.1007/978-3-642-28720-6_205] [PMID: 22389180]
[89]
Lidö HH, Marston H, Ericson M, Söderpalm B. The glycine reuptake inhibitor Org24598 and acamprosate reduce etha-nol intake in the rat; tolerance development to acamprosate but not to Org24598. Addict Biol 2012; 17(5): 897-907.
[http://dx.doi.org/10.1111/j.1369-1600.2011.00367.x] [PMID: 21955180]
[90]
Spanagel R, Bartsch D, Brors B, et al. An integrated genome research network for studying the genetics of alcohol ad-diction. Addict Biol 2010; 15(4): 369-79.
[http://dx.doi.org/10.1111/j.1369-1600.2010.00276.x] [PMID: 21040237]
[91]
Krystal JH, Petrakis IL, Limoncelli D, et al. Characterization of the interactive effects of glycine and D-cycloserine in men: Further evidence for enhanced NMDA receptor function associated with human alcohol dependence. Neuropsychopharmacology 2011; 36(3): 701-10.
[http://dx.doi.org/10.1038/npp.2010.203] [PMID: 21124304]
[92]
Gass JT, Olive MF. Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 2008; 75(1): 218-65.
[http://dx.doi.org/10.1016/j.bcp.2007.06.039] [PMID: 17706608]
[93]
Uslaner JM, Drott JT, Sharik SS, et al. Inhibition of glycine transporter 1 attenuates nicotine- but not food-induced cue-potentiated reinstatement for a response previously paired with sucrose. Behav Brain Res 2010; 207(1): 37-43.
[http://dx.doi.org/10.1016/j.bbr.2009.09.035] [PMID: 19799936]
[94]
Achat-Mendes C, Nic Dhonnchadha BÁ, Platt DM, Kantak KM, Spealman RD. Glycine transporter-1 inhibition preced-ing extinction training inhibits reacquisition of cocaine seeking. Neuropsychopharmacology 2012; 37(13): 2837-45.
[http://dx.doi.org/10.1038/npp.2012.155] [PMID: 22948980]
[95]
Nic Dhonnchadha BÁ, Pinard E, Alberati D, Wettstein JG, Spealman RD, Kantak KM. Inhibiting glycine transporter-1 facilitates cocaine-cue extinction and attenuates reacquisition of cocaine-seeking behavior. Drug Alcohol Depend 2012; 122(1-2): 119-26.
[http://dx.doi.org/10.1016/j.drugalcdep.2011.09.017] [PMID: 21992874]
[96]
Vengeliene V, Bachteler D, Danysz W, Spanagel R. The role of the NMDA receptor in alcohol relapse: A pharmacologi-cal mapping study using the alcohol deprivation effect. Neuropharmacology 2005; 48(6): 822-9.
[http://dx.doi.org/10.1016/j.neuropharm.2005.01.002] [PMID: 15829254]
[97]
Sesack SR, Grace AA. Cortico-basal ganglia reward network: Microcircuitry. Neuropsychopharmacology 2010; 35(1): 27-47.
[http://dx.doi.org/10.1038/npp.2009.93] [PMID: 19675534]
[98]
Harsing LG Jr, Gacsalyi I, Szabo G, et al. The glycine transporter-1 inhibitors NFPS and Org 24461: A pharmacological study. Pharmacol Biochem Behav 2003; 74(4): 811-25.
[http://dx.doi.org/10.1016/S0091-3057(02)01078-X] [PMID: 12667895]
[99]
Nong Y, Huang YQ, Ju W, et al. Glycine binding primes NMDA receptor internalization. Nature 2003; 422(6929): 302-7.
[http://dx.doi.org/10.1038/nature01497] [PMID: 12646920]
[100]
Umbricht D, Alberati D, Martin-Facklam M, et al. Effect of bitopertin, a glycine reuptake inhibitor, on negative symp-toms of schizophrenia: A randomized, double-blind, proof-of-concept study. JAMA Psychiatry 2014; 71(6): 637-46.
[http://dx.doi.org/10.1001/jamapsychiatry.2014.163] [PMID: 24696094]
[101]
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.
[http://dx.doi.org/10.1016/j.brainres.2011.03.051] [PMID: 21443867]
[102]
Martin-Facklam M, Pizzagalli F, Zhou Y, et al. Glycine transporter type 1 occupancy by bitopertin: A positron emission tomography study in healthy volunteers. Neuropsychopharmacology 2013; 38(3): 504-12.
[http://dx.doi.org/10.1038/npp.2012.212] [PMID: 23132267]
[103]
Umbricht D, Martin-Facklam M, Youssef E, et al. P.3.e.009 Glycine Reuptake Inhibitor RG1678: Results of the proof-of-concept study for the treatment of negative symptoms in schizophrenia. Eur Neuropsychopharmacol 2011; 21: S517-8.
[http://dx.doi.org/10.1016/S0924-977X(11)70841-0]
[104]
Eddins D, Hamill TG, Puri V, et al. The relationship between glycine transporter 1 occupancy and the effects of the gly-cine transporter 1 inhibitor RG1678 or ORG25935 on object retrieval performance in scopolamine impaired rhesus monkey. Psychopharmacology (Berl) 2014; 231(3): 511-9.
[http://dx.doi.org/10.1007/s00213-013-3260-0] [PMID: 24051602]
[105]
Harada K, Nakato K, Yarimizu J, et al. A novel glycine transporter-1 (GlyT1) inhibitor, ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole), improves cognition in animal models of cognitive im-pairment in schizophrenia and Alzheimer’s disease. Eur J Pharmacol 2012; 685(1-3): 59-69.
[http://dx.doi.org/10.1016/j.ejphar.2012.04.013] [PMID: 22542656]
[106]
Alberati D, Moreau JL, Lengyel J, et al. Glycine reuptake inhibitor RG1678: A pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology 2012; 62(2): 1152-61.
[http://dx.doi.org/10.1016/j.neuropharm.2011.11.008] [PMID: 22138164]
[107]
Liem-Moolenaar M, Peeters P, Kamerling IMC, et al. Early stage development of the glycine-1 re-uptake inhibitor SCH 900435: Central nervous system effects compared with placebo in healthy men. Br J Clin Pharmacol 2013; 75(6): 1455-67.
[http://dx.doi.org/10.1111/bcp.12015] [PMID: 23116363]
[108]
Ouellet D, Sutherland S, Wang T, Griffini P, Murthy V. First-time-in-human study with GSK1018921, a selective GlyT1 inhibitor: Relationship between exposure and dizziness. Clin Pharmacol Ther 2011; 90(4): 597-604.
[http://dx.doi.org/10.1038/clpt.2011.154] [PMID: 21866096]
[109]
Shen W, Jiang Z. Characterization of glycinergic synapses in vertebrate retinas. J Biomed Sci 2007; 14(1): 5-13.
[http://dx.doi.org/10.1007/s11373-006-9118-2] [PMID: 17061147]
[110]
de Bejczy A, Nations KR, Szegedi A, Schoemaker J, Ruwe F, Söderpalm B. Efficacy and safety of the glycine trans-porter-1 inhibitor org 25935 for the prevention of relapse in alcohol-dependent patients: a randomized, double-blind, placebo-controlled trial. Alcohol Clin Exp Res 2014; 38(9): 2427-35.
[http://dx.doi.org/10.1111/acer.12501] [PMID: 25257291]
[111]
D’Souza DC. Pilot Study of org 25935 modulation of ketamine-induced behavioral and cognitive effects in healthy male subjects NCT00700076, 2008 Available from: https://clinicaltrials.gov/ct2/show/NCT00700076?term =Org25935&draw=2&rank=1.
[112]
Bugarski-Kirola D, Blaettler T, Arango C, et al. Bitopertin in negative symptoms of schizophrenia-results from the phase III flashlyte and daylyte studies. Biol Psychiatry 2017; 82(1): 8-16.
[http://dx.doi.org/10.1016/j.biopsych.2016.11.014] [PMID: 28117049]
[113]
Lin C-Y, Tsai GE, Lane H-Y. Assessing and treating cognitive impairment in schizophrenia: Current and future. Curr Pharm Des 2014; 20(32): 5127-38.
[http://dx.doi.org/10.2174/1381612819666140110120015] [PMID: 24410565]
[114]
Strzelecki D, Podgórski M, Kałużyńska O, et al. Adding sarcosine to antipsychotic treatment in patients with stable schizophrenia changes the concentrations of neuronal and glial metabolites in the left dorsolateral prefrontal cortex. Int J Mol Sci 2015; 16(10): 24475-89.
[http://dx.doi.org/10.3390/ijms161024475] [PMID: 26501260]
[115]
Rehm J, Rehm M, Alho H, et al. Alcohol Dependence treatment in the eu: A literature search and expert consultation about the availability and use of guidelines in all eu countries plus iceland, norway, and switzerland. Int J Alcohol Drug Res 2013; 2(2): 53-67.
[http://dx.doi.org/10.7895/ijadr.v2i2.89]
[116]
Mark TL, Kranzler HR, Poole VH, Hagen CA, McLeod C, Crosse S. Barriers to the use of medications to treat alcohol-ism. Am J Addict 2003; 12(4): 281-94.
[http://dx.doi.org/10.1111/j.1521-0391.2003.tb00543.x] [PMID: 14504021]
[117]
Mark TL, Kassed CA, Vandivort-Warren R, Levit KR, Kranzler HR. Alcohol and opioid dependence medications: pre-scription trends, overall and by physician specialty. Drug Alcohol Depend 2009; 99(1-3): 345-9.
[http://dx.doi.org/10.1016/j.drugalcdep.2008.07.018] [PMID: 18819759]
[118]
National Collaborating Centre of Mental Health Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence 2011. 1-51. Available from: https://www.webcitation. org/60V1FV0Lm
[119]
Drummond C, Oyefeso A, Phillips T, et al. Alcohol needs assessment research project (ANARP): The 2004 national alcohol needs assessment for England. In: Nutritional Neuroscience. London: Department of Health 2005. 5. Available from: http://www.dh.gov.uk/en/Publi cationsandstatistics/Publications/PublicationsPolicy AndGuid-ance/DH_4122341?IdcService=GET_FILE&dID=5841&Rendition=Web.
[120]
Raistrick D, Heather N, Godfrey C. Review of the Effectiveness of Treatment for Alcohol Problems London: National Treatment Agency for Substance Misuse 2006. Available from: https://www.drugsandalcohol.ie/6153/
[121]
Zafra F, Giménez C. Glycine transporters and synaptic function. IUBMB Life 2008; 60(12): 810-7.
[http://dx.doi.org/10.1002/iub.128] [PMID: 18798526]