Hostname: page-component-586b7cd67f-dlnhk Total loading time: 0 Render date: 2024-11-24T07:59:14.948Z Has data issue: false hasContentIssue false
  • English
  • Français

The role of dopamine D3 receptors in the mechanism of action of cariprazine

Published online by Cambridge University Press:  23 April 2019

Francesca Calabrese ,
Frank I. Tarazi Open the ORCID record for Frank I. Tarazi [Opens in a new window] ,
Giorgio Racagni  and
Marco A. Riva Open the ORCID record for Marco A. Riva [Opens in a new window]
Francesca Calabrese
Affiliation:
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
Frank I. Tarazi
Affiliation:
Department of Psychiatry and Neuroscience Program, Harvard Medical School and McLean Hospital, Boston, MA, USA
Giorgio Racagni
Affiliation:
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy Associazione di Psicofarmacologia, Milan, Italy
Marco A. Riva*
Affiliation:
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
*
*Address correspondence to: Marco A. Riva, Professor, Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133Milan, Italy. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Cariprazine is a new atypical antipsychotic drug (APD) with a unique pharmacodynamic profile, different from both typical and atypical APDs. Specifically, cariprazine acts as a partial agonist at the dopamine (DA) D2 and D3 receptors and serotonin 5-HT1A receptors, and as an antagonist at the 5-HT2B receptors. Moreover, it shows moderate affinities for adrenergic, histaminergic, and cholinergic receptors that are involved in mediating the side effects characteristic of typical APDs. In this review, we discuss the contribution of DA D3 receptors (D3Rs) in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of D3R by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes. Cariprazine, by acting on D3Rs, ameliorates anhedonia and cognitive deficits in animal models based on environmental or pharmacological manipulation. The reviewed results support the potential benefits of cariprazine in treating negative symptoms and cognitive deficits of schizophrenia, and therefore representing a promising approach in addressing the unmet clinical needs for the improved treatment of this serious neuropsychiatric disorder.

Keywords

Dopamine D3 receptorscariprazineantipsychotic drugsschizophrenianegative symptomscognitive deficits
Type
Review
Information
CNS Spectrums , Volume 25 , Issue 3 , June 2020 , pp. 343 - 351
Copyright
© Cambridge University Press 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References:

Biesdorf, C, Wang, AL, Topic, B, et al.Dopamine in the nucleus accumbens core, but not shell, increases during signaled food reward and decreases during delayed extinction. Neurobiol Learn Mem. 2015; 123: 125–139.Google Scholar
Cools, R, D’Esposito, M.Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry. 2011; 69(12): e113–e125.Google Scholar
Hamid, AA, Pettibone, JR, Mabrouk, OS, et al.Mesolimbic dopamine signals the value of work. Nat Neurosci. 2016; 19(1): 117–126.Google Scholar
Kegeles, LS, Abi-Dargham, A, Frankle, WG, et al.Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry. 2010; 67(3): 231–239.Google Scholar
Gingrich, JA, Caron, MG.Recent advances in the molecular biology of dopamine receptors. Annu Rev Neurosci. 1993; 16: 299–321.Google Scholar
Sibley, DR, Monsma, FJ Jr.Molecular biology of dopamine receptors. Trends Pharmacol Sci. 1992; 13(2): 61–69.Google Scholar
Beaulieu, JM, Gainetdinov, RR, Caron, MG.The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci. 2007; 28(4): 166–172.Google Scholar
Leucht, S, Davis, JM.Schizophrenia, primary negative symptoms, and soft outcomes in psychiatry. Lancet. 2017; 389(10074): 1077–1078.Google Scholar
Potkin, SG, Loze, JY, Forray, C, et al.Multidimensional assessment of functional outcomes in schizophrenia: results from QUALIFY, a head-to-head trial of aripiprazole once-monthly and paliperidone palmitate. Int J Neuropsychopharmacol. 2017; 20(1): 40–49.Google Scholar
Nemeth, G, Laszlovszky, I, Czobor, P, et al.Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017; 389(10074): 1103–1113.Google Scholar
Tsapakis, EM, Dimopoulou, T, Tarazi, FI.Clinical management of negative symptoms of schizophrenia: an update. Pharmacol Ther. 2015; 153: 135–147.Google Scholar
Sokoloff, P, Giros, B, Martres, MP, Bouthenet, ML, Schwartz, JC.Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 1990; 347(6289): 146–151.Google Scholar
Gurevich, EV, Joyce, JN.Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology. 1999; 20(1): 60–80.Google Scholar
Sokoloff, P, Le Foll, B.The dopamine D3 receptor, a quarter century later. Eur J Neurosci. 2017; 45(1): 2–19.Google Scholar
Sokoloff, P, Diaz, J, Le Foll, B, et al.The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets. 2006; 5(1): 25–43.Google Scholar
Stahl, SM.Dazzled by the dominions of dopamine: clinical roles of D3, D2, and D1 receptors. CNS Spectr. 2017; 22(4): 305–311.Google Scholar
Grace, AA.Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci. 2016; 17(8): 524–532.Google Scholar
Kapur, S.Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003; 160(1): 13–23.Google Scholar
Maggio, R, Scarselli, M, Capannolo, M, Millan, MJ.Novel dimensions of D3 receptor function: focus on heterodimerisation, transactivation and allosteric modulation. Eur Neuropsychopharmacol. 2015; 25(9): 1470–1479.Google Scholar
Scarselli, M, Novi, F, Schallmach, E, et al.D2/D3 dopamine receptor heterodimers exhibit unique functional properties. J Biol Chem. 2001; 276(32): 30308–30314.Google Scholar
Fiorentini, C, Busi, C, Spano, P, Missale, C.Role of receptor heterodimers in the development of L-dopa-induced dyskinesias in the 6-hydroxydopamine rat model of Parkinson’s disease. Parkinsonism Relat Disord. 2008; 14(Suppl 2): S159–S164.Google Scholar
Marcellino, D, Ferre, S, Casado, V, et al.Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum. J Biol Chem. 2008; 283(38): 26016–26025.Google Scholar
Torvinen, M, Marcellino, D, Canals, M, et al.Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes. Mol Pharmacol. 2005; 67(2): 400–407.Google Scholar
Collo, G, Bono, F, Cavalleri, L, et al.Nicotine-induced structural plasticity in mesencephalic dopaminergic neurons is mediated by dopamine D3 receptors and Akt-mTORC1 signaling. Mol Pharmacol. 2013; 83(6): 1176–1189.Google Scholar
Cussac, D, Newman-Tancredi, A, Pasteau, V, Millan, MJ.Human dopamine D(3) receptors mediate mitogen-activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism. Mol Pharmacol. 1999; 56(5): 1025–1030.Google Scholar
Collo, G, Zanetti, S, Missale, C, Spano, P.Dopamine D3 receptor-preferring agonists increase dendrite arborization of mesencephalic dopaminergic neurons via extracellular signal-regulated kinase phosphorylation. Eur J Neurosci. 2008; 28(7): 1231–1240.Google Scholar
Schwartz, JC, Diaz, J, Pilon, C, Sokoloff, P.Possible implications of the dopamine D(3) receptor in schizophrenia and in antipsychotic drug actions. Brain Res Brain Res Rev. 2000; 31(2-3): 277–287.Google Scholar
Gyertyan, I, Saghy, K.Effects of dopamine D3 receptor antagonists on spontaneous and agonist-reduced motor activity in NMRI mice and Wistar rats: comparative study with nafadotride, U 99194A and SB 277011. Behav Pharmacol. 2004; 15(4): 253–262.Google Scholar
Nakajima, S, Gerretsen, P, Takeuchi, H, et al.The potential role of dopamine D(3) receptor neurotransmission in cognition. Eur Neuropsychopharmacol. 2013; 23(8): 799–813.Google Scholar
Barth, V, Need, AB, Tzavara, ET, et al. In vivo occupancy of dopamine D3 receptors by antagonists produces neurochemical and behavioral effects of potential relevance to attention-deficit-hyperactivity disorder. J Pharmacol Exp Ther. 2013; 344(2): 501–510.Google Scholar
Laszy, J, Laszlovszky, I, Gyertyan, I.Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl). 2005; 179(3): 567–575.Google Scholar
Millan, MJ, Di Cara, B, Dekeyne, A, et al.Selective blockade of dopamine D(3) versus D(2) receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis. J Neurochem. 2007; 100(4): 1047–1061.Google Scholar
Watson, DJ, Loiseau, F, Ingallinesi, M, Millan, MJ, Marsden, CA, Fone, KC.Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex. Neuropsychopharmacology. 2012; 37(3): 770–786.Google Scholar
Lumme, V, Aalto, S, Ilonen, T, Nagren, K, Hietala, J.Dopamine D2/D3 receptor binding in the anterior cingulate cortex and executive functioning. Psychiatry Res. 2007; 156(1): 69–74.Google Scholar
Simpson, EH, Winiger, V, Biezonski, DK, Haq, I, Kandel, ER, Kellendonk, C.Selective overexpression of dopamine D3 receptors in the striatum disrupts motivation but not cognition. Biol Psychiatry. 2014; 76(10): 823–831.Google Scholar
Gross, G, Wicke, K, Drescher, KU.Dopamine D(3) receptor antagonism--still a therapeutic option for the treatment of schizophrenia. Naunyn Schmiedebergs Arch Pharmacol. 2013; 386(2): 155–166.Google Scholar
Joyce, JN, Millan, MJ.Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov Today. 2005; 10(13): 917–925.Google Scholar
Van Kampen, JM, Eckman, CB. Dopamine D3 receptor agonist delivery to a model of Parkinson’s disease restores the nigrostriatal pathway and improves locomotor behavior. J Neurosci. 2006; 26(27): 7272–7280.Google Scholar
Mailman, RB, Murthy, V.Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Curr Pharm Des. 2010; 16(5): 488–501.Google Scholar
Pich, EM, Collo, G.Pharmacological targeting of dopamine D3 receptors: possible clinical applications of selective drugs. Eur Neuropsychopharmacol. 2015; 25(9): 1437–1447.Google Scholar
Frankel, JS, Schwartz, TL.Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole. Ther Adv Psychopharmacol. 2017; 7(1): 29–41.Google Scholar
Miyamoto, S, Duncan, GE, Marx, CE, Lieberman, JA.Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005; 10(1): 79–104.Google Scholar
Kiss, B, Horvath, A, Nemethy, Z, et al.Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010; 333(1): 328–340.Google Scholar
Veselinovic, T, Paulzen, M, Grunder, G.Cariprazine, a new, orally active dopamine D2/3 receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression. Expert Rev Neurother. 2013; 13(11): 1141–1159.Google Scholar
Goff, DC.Brexpiprazole: a new antipsychotic following in the footsteps of aripiprazole. Am J Psychiatry. 2015; 172(9): 820–821.Google Scholar
Stahl, SM.Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes. CNS Spectr. 2017; 22(5): 375–384.Google Scholar
Nakamura, T, Kubota, T, Iwakaji, A, Imada, M, Kapas, M, Morio, Y.Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment). Drug Des Devel Ther. 2016; 10: 327–338.Google Scholar
Garnock-Jones, KP.Cariprazine: a review in schizophrenia. CNS Drugs. 2017; 31(6): 513–525.Google Scholar
De Berardis, D, Orsolini, L, Iasevoli, F, et al.The novel antipsychotic cariprazine (RGH-188): State-of-the-art in the treatment of psychiatric disorders. Curr Pharm Des. 2016; 22(33): 5144–5162.Google Scholar
Calabrese, JR, Keck, PE Jr., Starace, A, et al.Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2015; 76(3): 284–292.Google Scholar
Durgam, S, Cutler, AJ, Lu, K, et al.Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial. J Clin Psychiatry. 2015; 76(12):e1574–e1582.Google Scholar
Durgam, S, Greenberg, WM, Li, D, et al.Safety and tolerability of cariprazine in the long-term treatment of schizophrenia: results from a 48-week, single-arm, open-label extension study. Psychopharmacology (Berl). 2017; 234(2): 199–209.Google Scholar
Durgam, S, Starace, A, Li, D, et al.An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014; 152(2-3): 450–457.Google Scholar
Kane, JM, Zukin, S, Wang, Y, et al.Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: Results from an international, phase III clinical trial. J Clin Psychopharmacol. 2015; 35(4): 367–373.Google Scholar
Cutler, AJ, Durgam, S, Wang, Y, et al.Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-year open-label study. CNS Spectr. 2017: 1–12.Google Scholar
Ketter, TA, Sachs, GS, Durgam, S, et al.The safety and tolerability of cariprazine in patients with manic or mixed episodes associated with bipolar I disorder: A 16-week open-label study. J Affect Disord. 2018; 225: 350–356.Google Scholar
Earley, W, Durgam, S, Lu, K, Laszlovszky, I, Debelle, M, Kane, JM.Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double-blind, placebo-controlled studies. Int Clin Psychopharmacol. 2017; 32(6): 319–328.Google Scholar
Nasrallah, HA, Earley, W, Cutler, AJ, et al.The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis. BMC Psychiatry. 2017; 17(1): 305.Google Scholar
Buchanan, RW, Breier, A, Kirkpatrick, B, Ball, P, Carpenter, WT Jr.Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry. 1998; 155(6): 751–760.Google Scholar
Nemeth, B, Molnar, A, Akehurst, R, et al.Quality-adjusted life year difference in patients with predominant negative symptoms of schizophrenia treated with cariprazine and risperidone. J Comp Eff Res. 2017; 6(8): 639–648.Google Scholar
Choi, YK, Adham, N, Kiss, B, Gyertyan, I, Tarazi, FI.Long-term effects of cariprazine exposure on dopamine receptor subtypes. CNS Spectr. 2014; 19(3): 268–277.Google Scholar
Tarazi, FI, Florijn, WJ, Creese, I.Differential regulation of dopamine receptors after chronic typical and atypical antipsychotic drug treatment. Neuroscience. 1997; 78(4): 985–996.Google Scholar
Tarazi, FI, Yeghiayan, SK, Baldessarini, RJ, Kula, NS, Neumeyer, JL.Long-term effects of S(+)N-n-propylnorapomorphine compared with typical and atypical antipsychotics: differential increases of cerebrocortical D2-like and striatolimbic D4-like dopamine receptors. Neuropsychopharmacology. 1997; 17(3): 186–196.Google Scholar
Tarazi, FI, Zhang, K, Baldessarini, RJ.Long-term effects of olanzapine, risperidone, and quetiapine on dopamine receptor types in regions of rat brain: implications for antipsychotic drug treatment. J Pharmacol Exp Ther. 2001; 297(2): 711–717.Google Scholar
Tarazi, FI, Moran-Gates, T, Wong, EH, Henry, B, Shahid, M.Differential regional and dose-related effects of asenapine on dopamine receptor subtypes. Psychopharmacology (Berl). 2008; 198(1): 103–111.Google Scholar
Gyertyan, I, Kiss, B, Saghy, K, et al.Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents. Neurochem Int. 2011; 59(6): 925–935.Google Scholar
Zhang, K, Weiss, NT, Tarazi, FI, Kula, NS, Baldessarini, RJ.Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine. Brain Res. 1999; 847(1): 32–37.Google Scholar
Harvey, PD, Wingo, AP, Burdick, KE, Baldessarini, RJ.Cognition and disability in bipolar disorder: lessons from schizophrenia research. Bipolar Disord. 2010; 12(4): 364–375.Google Scholar
Baldessarini, RJ, Tarazi, FI.Pharmacotherapy of psychosis and mania. In: Brunton, LL, Lazo, JS, Parker, KL, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed.New York: McGraw-Hill; 2005:461–500.Google Scholar
Citrome, L.Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013; 30(2): 114–126.Google Scholar
Citrome, L.Cariprazine in bipolar disorder: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013; 30(2): 102–113.Google Scholar
Choi, YK, Adham, N, Kiss, B, Gyertyan, I, Tarazi, FI.Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine. CNS Spectr. 2017: 1–11.Google Scholar
Tarazi, FI, Zhang, K, Baldessarini, RJ.Long-term effects of olanzapine, risperidone, and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain regions. Psychopharmacology (Berl). 2002; 161(3): 263–270.Google Scholar
Tarazi, FI, Baldessarini, RJ, Kula, NS, Zhang, K.Long-term effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: implications for antipsychotic drug treatment. J Pharmacol Exp Ther. 2003; 306(3): 1145–1151.Google Scholar
Tarazi, FI, Choi, YK, Gardner, M, Wong, EH, Henry, B, Shahid, M.Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain. Synapse. 2009; 63(5): 413–420.Google Scholar
Tarazi, FI, Florijn, WJ, Creese, I.Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics. Psychopharmacology (Berl). 1996; 128(4): 371–379.Google Scholar
Tarsy, D, Baldessarini, RJ, Tarazi, FI.Effects of newer antipsychotics on extrapyramidal function. CNS Drugs. 2002; 16(1): 23–45.Google Scholar
Tsai, G, Coyle, JT.Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol. 2002; 42: 165–179.Google Scholar
Zimnisky, R, Chang, G, Gyertyan, I, Kiss, B, Adham, N, Schmauss, C.Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology (Berl). 2013; 226(1): 91–100.Google Scholar
Barnes, SA, Young, JW, Markou, A, Adham, N, Gyertyan, I, Kiss, B.The effects of cariprazine and aripiprazole on PCP-induced deficits on attention assessed in the 5-choice serial reaction time task. Psychopharmacology (Berl). 2018; 235(5): 1403–1414.Google Scholar
Neill, JC, Grayson, B, Kiss, B, Gyertyan, I, Ferguson, P, Adham, N.Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology. Eur Neuropsychopharmacol. 2016; 26(1): 3–14.Google Scholar
Reinwald, JR, Becker, R, Mallien, AS, et al.Neural mechanisms of early-life social stress as a developmental risk factor for severe psychiatric disorders. Biol Psychiatry. 2017.Google Scholar
Watson, DJG, King, MV, Gyertyan, I, Kiss, B, Adham, N, Fone, KCF.The dopamine D(3)-preferring D(2)/D(3) dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia. Eur Neuropsychopharmacol. 2016; 26(2): 208–224.Google Scholar
Duric, V, Banasr, M, Franklin, T, et al.Cariprazine exhibits anxiolytic and dopamine D3 receptor-dependent antidepressant effects in the chronic stress model. Int J Neuropsychopharmacol. 2017; 20(10): 788–796.Google Scholar
Papp, M, Gruca, P, Lason-Tyburkiewicz, M, Adham, N, Kiss, B, Gyertyan, I.Attenuation of anhedonia by cariprazine in the chronic mild stress model of depression. Behav Pharmacol. 2014; 25(5-6): 567–574.Google Scholar
Chourbaji, S, Brandwein, C, Vogt, MA, et al.Dopamine receptor 3 (D3) knockout mice show regular emotional behaviour. Pharmacol Res. 2008; 58(5-6): 302–307.Google Scholar
Leggio, GM, Micale, V, Drago, F.Increased sensitivity to antidepressants of D3 dopamine receptor-deficient mice in the forced swim test (FST). Eur Neuropsychopharmacol. 2008; 18(4): 271–277.Google Scholar
Meltzer, HY, Huang, M, He, W, Kiss, B, Farkas, B, Adham, N.Cariprazine enhances monoaminergic activity in the hippocampus and ventral striatum of rats: A possible basis for its antipsychotic effect. Biol Psychiatry 2018; 83(9, supplement): S228.Google Scholar