• Anton J. M. Loonen Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands
  • Svetlana A. Ivanova Mental Health Research Institute National Research Tomsk Polytechnic University


By integrating knowledge gained by pharmacogenetic, neuroanatomical and pharmacological studies, a model can be constructed how serotonin (5-HT) affects the vulnerability to induce tardive dyskinesia. From neuroanatomical studies, it can be concluded that 5-HT inhibits the release of dopamine (DA) within the dorsal striatum by affecting 5-HT2C receptors and also within the ventral striatum and prefrontal cortex by affecting 5-HT2A receptors. However, considering the low affinity of DA for its receptors, it is unlikely that the so released DA is able to displace atypical antipsychotics from DA D2 and D3 receptors. 5-HT2C receptors and, to a lesser extent, 5-HT2A receptors, have constitutive activity and therefore, atypical antipsychotics can have inverse agonistic effects. It is hypothesized that decreasing the activity of 5-HT2 receptor carrying medium spiny neurons (MSNs) within the dorsal striatum represents the mechanism showing how atypical antipsychotics have limited ability to cause tardive dyskinesia.


Keywords: Tardive dyskinesia, Extrapyramidal system, Medium spiny neurons, 5-HT2C receptors, Inverse agonism


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1. Loonen AJ, van Praag HM. Measuring movement disorders in antipsychotic drug trials: the need to define a new standard. J Clin Psychopharmacol 2007;27:423-30.
2. Aquino CC, Lang AE. Tardive dyskinesia syndromes: current concepts. Parkinsonism Related Disorders 2014;20 Suppl 1:S113-7.
3. Clark GT, Ram S. Four oral motor disorders: bruxism, dystonia, dyskinesia and drug-induced dystonic extrapyramidal reactions. Dent Clin North Am 2007;51:225-43.
4. Woerner MG, Kane JM, Lieberman JA, Alvir J, Bergmann KJ, Borenstein M, et al. The prevalence of tardive dyskinesia. J Clin Psychopharmacol 1991;11:34-42.
5. Kane JM, Smith JM. Tardive dyskinesia: prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry 1982;39:473-81.
6. Pappa S, Dazzan P. Spontaneous movement disorders in antipsychotic-naive patients with first-episode psychoses: a systematic review. Psychol Med 2009;39:1065-76.
7. Tenback DE, van Harten PN. Epidemiology and risk factors for (tardive) dyskinesia. Int Rev Neurobiol 2011;98:211-30.
8. Wild EJ, Tabrizi SJ. The differential diagnosis of chorea. Pract Neurol 2007;7:360-73.
9. Zesiewicz TA, Sullivan KL. Drug-induced hyperkinetic movement disorders by nonneuroleptic agents. Handb Clin Neurol 2011;100:347-63.
10. Loonen AJ, Ivanova SA. New insights into the mechanism of drug-induced dyskinesia. CNS Spectrums 2013;18:15-20.
11. Bargiotas P, Konitsiotis S. Levodopa-induced dyskinesias in Parkinson's disease: emerging treatments. Neuropsychiatr Dis Treat 2013;9:1605-17.
12. Del Sorbo F, Albanese A. Levodopa-induced dyskinesias and their management. J Neurol 2008;255 Suppl 4:32-41.
13. Manson A, Stirpe P, Schrag A. Levodopa-induced-dyskinesias clinical features, incidence, risk factors, management and impact on quality of life. J Parkinson's Dis 2012;2:189-98.
14. Thanvi BR, Lo TC. Long term motor complications of levodopa: clinical features, mechanisms, and management strategies. Postgrad Med J 2004;80:452-8.
15. Glazer WM. Extrapyramidal side effects, tardive dyskinesia, and the concept of atypicality. J Clin Psychiatry 2000;61 Suppl 3:16-21.
16. Cheshire PA, Williams DR. Serotonergic involvement in levodopa-induced dyskinesias in Parkinson's disease. J Clin Neurosci 2012;19:343-8.
17. Huot P, Johnston TH, Koprich JB, Fox SH, Brotchie JM. The pharmacology of L-DOPA-induced dyskinesia in Parkinson's disease. Pharmacol Rev 2013;65:171-222.
18. Sandyk R, Fisher H. Serotonin in involuntary movement disorders. Int J Neurosci 1988;42:185-208.
19. Loonen AJ. Het beweeglijke brein. De neurowetenschappelijke achtergronden van de psychische functies. Haarlem, NL: Mension Publisher; 2013.
20. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002;71:533-54.
21. Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behav Brain Res 2008;195:198-213.
22. Meltzer HY. Serotonergic mechanisms as targets for existing and novel antipsychotics. In: G Gross, MA Geyer. (eds.) Current antipsychotics. Handb Exp Pharmacol 2012;212:87-124.
23. Stiedl O, Pappa E, Konradsson-Geuken Å, Ögren SO. The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory. Front Pharmacol 2015;6:162.
24. Howell LL, Cunningham KA. Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol Rev 2015;67:176-97.
25. Arranz MJ, Rivera M, Munro JC. Pharmacogenetics of response to antipsychotics in patients with schizophrenia. CNS Drugs 2011;25:933-69.
26. Al Hadithy AF, Wilffert B, Stewart RE, Looman NM, Bruggeman R, Brouwers JR, et al. Pharmacogenetics of parkinsonism, rigidity, rest tremor, and bradykinesia in African-Caribbean inpatients: differences in association with dopamine and serotonin receptors. Am J Med Genet Part B 2008;5;147B:890-7.
27. Al Hadithy AF, Wilffert B, Bruggeman R, Stewart RE, Brouwers JR, Matroos GE, et al. Lack of association between antipsychotic-induced Parkinsonism or its subsymptoms and rs4606 SNP of RGS2 gene in African-Caribbeans and the possible role of the medication: the Curacao extrapyramidal syndromes study X. Hum Psychopharmacol 2009;24:123-8.
28. Gunes A, Dahl ML, Spina E, Scordo MG. Further evidence for the association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients. Eur J Clin Pharmacol 2008;64:477-82.
29. Segman RH, Heresco-Levy U, Finkel B, Inbar R, Neeman T, Schlafman M, et al. Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility. Psychopharmacology (Berl) 2000;152:408-13.
30. Wilffert B, Al Hadithy AF, Sing VJ, Matroos G, Hoek HW, van Os J, et al. The role of dopamine D3, 5-HT2A and 5-HT2C receptor variants as pharmacogenetic determinants in tardive dyskinesia in African-Caribbean patients under chronic antipsychotic treatment: Curacao extrapyramidal syndromes study IX. J Psychopharmacol 2009;23:652-9.
31. Milatovich A, Hsieh CL, Bonaminio G, Tecott L, Julius D, Francke U. Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). Hum Mol Genet 1992;1:681-4.
32. Segman R, Neeman T, Heresco-Levy U, Finkel B, Karagichev L, Schlafman M, et al. Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 1999;4:247-53.
33. Duinkerke SJ, Botter PA, Jansen AA, van Dongen PA, van Haaften AJ, Boom AJ, et al. Ritanserin, a selective 5-HT2/1C antagonist, and negative symptoms in schizophrenia. A placebo-controlled double-blind trial. Br J Psychiatry 1993;163:451-5.
34. Grant S, Fitton A. Risperidone. A review of its pharmacology and therapeutic potential in the treatment of schizophrenia. Drugs 1994;48:253-73.
35. Owens DG. Extrapyramidal side effects and tolerability of risperidone: a review. J Clin Psychiatry 1994;55 Suppl:29-35.
36. Leysen JE. 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord 2004;3:11-26.
37. Nieuwenhuys R. Chemoarchitecture of the brain. Berlin: Springer-Verlag; 1985.
38. Aloyo VJ, Berg KA, Spampinato U, Clarke WP, Harvey JA. Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacol Ther 2009;121:160-73.
39. Celada P, Puig MV, Artigas F. Serotonin modulation of cortical neurons and networks. Front Integr Neurosci 2013;7:25.
40. Blomeley CP, Bracci E. Serotonin excites fast-spiking interneurons in the striatum. Eur J Neurosci 2009;29:1604-14.
41. Eberle-Wang K, Mikeladze Z, Uryu K, Chesselet MF. The pattern of expression of the serotonin2C receptor messenger RNA in the basal ganglia of adult rats. J Comp Neurol 1997;384:233-47.
42. Ikemoto K, Nishimura A, Okado N, Mikuni M, Nishi K, Nagatsu I. Human midbrain dopamine neurons express serotonin 2A receptor: an immunohistochemical demonstration. Brain Res 2000;853:377-80.
43. Nocjar C, Roth BL, Pehek EA. Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group. Neuroscience 2002;111:163-76.
44. Muramatsu M, Tamaki-Ohashi J, Usuki C, Araki H, Chaki S, Aihara H. 5-HT2 antagonists and minaprine block the 5-HT-induced inhibition of dopamine release from rat brain striatal slices. Eur J Pharmacol 1988;153:89-95.
45. Di Matteo V, Di Giovanni G, Pierucci M, Esposito E. Serotonin control of central dopaminergic function: focus on in vivo microdialysis studies. Prog Brain Res 2008;172:7-44.
46. Di Matteo V, Pierucci M, Esposito E, Crescimanno G, Benigno A, Di Giovanni G. Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders. Prog Brain Res 2008;172:423-63.
47. Fink KB, Göthert M. 5-HT receptor regulation of neurotransmitter release. Pharmacol Rev 2007;59:360-417.
48. Casey DE. Pathophysiology of antipsychotic drug-induced movement disorders. J Clin Psychiatry 2004;65 Suppl9:25-8.
49. Seeman P. Brain dopamine receptors. Pharmacol Rev 1980;32:229-313.
50. Chwieduk CM, Scott LJ. Asenapine: a review of its use in the management of mania in adults with bipolar I disorder. CNS Drugs 2011;25:251-67.
51. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 1996;124:57-73.
52. Leysen JE. Receptors for antipsychotic drugs. In: GD Burrows, JS Werry. (eds). Adv Hum Psychopharmacology. Greenwich, CT: JAI Press Inc; 1982.
53. Oekelen DV, Jurzak M, Van de Wiel D, Van Hecke G, Luyten WH, Leysen JE. Different regulation of rat 5-HT(2A) and rat 5-HT(2C) receptors in NIH 3T3 cells upon exposure to 5-HT and pipamperone. Eur J Pharmacol 2001;425:21-32.
54. Leysen JE, Gommeren W, Van Gompel P, Wynants J, Janssen PF, Laduron PM. Receptor-binding properties in vitro and in vivo of ritanserin: A very potent and long-acting serotonin-S2 antagonist. Mol Pharmacol 1985;27:600-11.
55. Arnt J, Skarsfeldt T. Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 1998;18:63-101.
56. Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996;14:87-96.
57. Richtand NM, Welge JA, Logue AD, Keck PE Jr, Strakowski SM, McNamara RK. The role of serotonin and dopamine receptor binding in antipsychotic efficacy. Prog Brain Res 2008;172:155-75.
58. Sullivan LC, Clarke WP, Berg KA. Atypical antipsychotics and inverse agonism at 5-HT2 receptors. Curr Pharm Des 2015;21:3732-8.
59. Lencz T, Malhotra AK. Pharmacogenetics of antipsychotic-induced side effects. Dialogues Clin Neurosci 2009;11:405-15.
60. Lundstrom K, Turpin MP. Proposed schizophrenia-related gene polymorphism: expression of the Ser9Gly mutant human dopamine D3 receptor with the semliki forest virus system. Biochem Biophys Res Commun 1996;225:1068-72.
61. Schwartz JC, Levesque D, Martres MP, Sokoloff P. Dopamine D3 receptor: basic and clinical aspects. Clin Neuropharmacol 1993;16:295-314.
62. Richelson E. Pharmacology of antidepressants. Mayo Clin Proc 2001;76:511-27.
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How to Cite
Loonen, A. J. M., and S. A. Ivanova. “ROLE OF 5-HT2C RECEPTORS IN DYSKINESIA”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 8, no. 1, Nov. 2015, pp. 5-10,
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