Animal Models in Tardive Dyskinesia

  • Helen Rosengarten
  • Jack W. Schweitzer
  • Arnold J. Friedhoff
Part of the Neuromethods book series (NM, volume 18)


The introduction of neuroleptics in 1952 to clinical practice was followed by numerous reports in the literature describing a syndrome of abnormal involuntary movements that appeared with increasing frequency during treatment or during withdraw al from neuroleptics. This syndrome was first described in the late 1950s (Hall et al., 1956; Kullenkampf and Tarnow, 1956; Schoenecker, 1957; Sigwald et al., 1959) and these reversible and irreversible drug-related dyskinesias were subsequently named tardive dyskinesia (Uhrband and Faurbye, 1960). The role of neuroleptics as the cause of tardive dyskinesia remained controversial for many years; subsequently, a number of investigators concluded that chronic neuroleptic treatment may precipitate TD only in those patients who are already predisposed to the development of this disorder (Smith and Baldessarini, 1980; Itil et al., 1981; Kane and Smith, 1982; Marsden, 1985; Waddington et al., 1988; Toenniessen et al., 1985; Hanssen et al., 1988).


Tardive Dyskinesia Neuroleptic Treatment Tongue Protrusion Haloperidol Decanoate Fluphenazine Decanoate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Alpert M., Diamond F, and Friedhoff A. J. (1976) Tremographic studies in tardive dyskinesia. Psychopharmacol. Bull. 12, 5–7.PubMedGoogle Scholar
  2. Arnt J. and Scheel-Kruger J. (1980) Intranigral GABA antagonists produce dopamine independent biting in rats. Eur. J. Pharmacol. 62, 51–61.PubMedCrossRefGoogle Scholar
  3. Arnt J. and Perregaard, J. (1985) Differential involvement of dopamine D1 and D2 receptors in circling behavior induced by apomorphine, SKF 38393, pergolide and LY 171555 in 6-hydroxylesioned rats. Psychopharmacology 85, 346–350.PubMedCrossRefGoogle Scholar
  4. Arnt J. (1987) Behavioral studies of dopamine receptors. Evidence for regional selectivity and receptor multiplicity, in Dopamine Receptors (Creese I. and Fraser C. A., eds.), Liss, New York, NY, pp. 199–207.Google Scholar
  5. Arnt J., Hyttel J., and Perregaard J. (1987) Dopamine D1 receptor agonist combined with the selective D2 agonist quinpirole facilitates the expression of oral stereotyped behavior in rats. Eur. J. Phurmacol, 133, 137–145.CrossRefGoogle Scholar
  6. Baldessarini R. J. and Tarsy D. (1976) Mechanism underlying tardive dyskinesia. In Basal Ganglia (Yahr M., ed.), Raven, NY, pp. 25–36.Google Scholar
  7. Baldessarini R. J. and Tarsy D. (1980) Dopamine and the pathophysiology of dyskinesia induced by antipsychotic drugs. Ann. Rrru. Neurawi. 3, 23–41.CrossRefGoogle Scholar
  8. Baldessarini R. J., Coke J. O., and Davis J. M. (1980) Report on the American Psychiatric Association Task Force on Late neurological effects of antipsychotic drugs, Washington, DC, American Psychiatric Association.Google Scholar
  9. Barany S., Ingvast A., and Gunne L. M. (1979) Development of acute dystonia and tardive dyskinesia in cebus monkeys. Res. Comm. Chem. Path. Pharmacol. 25, 269–279.Google Scholar
  10. Bedard P., Larochelle L., Delean I., and Lafleur I. (1972) Dyskinesias induced by long-term administration of haloperidol in the monkey. Physiologist 15, 83.Google Scholar
  11. Braun A. R. and Chase T. N. (1986) Obligatory D1/D2 receptor interaction in the generation of dopamine agonist-induced behaviors. Eur. J. Pharmacol. 131, 301–306.PubMedCrossRefGoogle Scholar
  12. Burt D. R., Creese I., and Snyder S. H. (1977) Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain. Science 196, 326–328.PubMedCrossRefGoogle Scholar
  13. Carpenter W. T., Rey A. C., and Stephens I. H. (1980) Covert dyskinesia in ambulatory Schizophrenia. Luncet 2, 212–213.CrossRefGoogle Scholar
  14. Casey D. E. and Denney D. (1977) Pharmacological characterization of tardive dyskinesia. Psychopharmacology 54 1–8.PubMedCrossRefGoogle Scholar
  15. Casey D. E. (1984) Tardive Dyskinesia—animal models. Psychoyharmacol. Bull. 20, 376–379.Google Scholar
  16. Casey D. E. (1985) Behavioral effects of long-term neuroleptic treatment in cebus monkeys, in Dyskinesia: Research and Treatment (Casey D. E., Chase T. N., Christensen A. V, and Gerlack J., eds.), Springer Verlag, Berlin, Heidelberg, pp. 211–216.Google Scholar
  17. Clow A., Jenner P., and Marsden C. D. (1979) Changes in dopamine mediated behavior during one year’s neuroleptic administration. Eur. J. Pharmacol. 57, 365–375.PubMedCrossRefGoogle Scholar
  18. Costall B. and Naylor R. B. (1974) The involvement of dopaminergic systems with the stereotyped behavior patterns induced by methylphenidate. J Pharm. Pharmacol. 26, 30–33.PubMedGoogle Scholar
  19. Creese I., Burt D. R., and Snyder S. H. (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192, 481–483.PubMedCrossRefGoogle Scholar
  20. Ellison G, See R., Levin E, and Kinney J. (1987) Tremulous mouth movements in rats administered chronic neuroleptics. Psychoyhumucwlogy 92, 122–126.Google Scholar
  21. Ellison G. and See R. E. (1989) Rats administered chronic neuroleptics develop oral movements which are similar in form to those in humans with tardive dyskinesia. Psychopharmacology 98, 564–566.PubMedCrossRefGoogle Scholar
  22. Fage E. and Scatton B. (1986) Effects of D1 and D2 receptor antagonists on acetylcholine levels in the rat striatum. Eur. J. Pharmacol. 129, 359–362.PubMedCrossRefGoogle Scholar
  23. Fann E., Stafford J., Malone R., Frost J., and Richman B. (1977) Clinical research techniques in tardive dyskinesia. Am. J Psychiatr. 134, 759–762.PubMedGoogle Scholar
  24. Farde L., Halldin C., Stone-Elander S., and Sedvall G. (1987) PET analysis of human dopamine receptors subtypes using 11-C-SCH 23390 and llC-raclopride. Psychophurmacology 92, 278–284.CrossRefGoogle Scholar
  25. Friedhoff A. J., Bonnet K., and Rosengarten H. (1977) Reversal of two manifestations of dopamine receptor supersensitivity by administration of L-Dopa. Res. Comm. Chem. Path. Pharmacol. 116, 411–423.Google Scholar
  26. Gale K. (1980) Chronic blockade of dopamine receptors by antischizophrenic drugs enhances G AB A binding in substantia nigra. Nature 283, 569–570.PubMedCrossRefGoogle Scholar
  27. Gardos G., Cole J. O., and Tarsy D. (1978) Withdrawl syndromes associated with antipsychotic drugs. Am. J. Psychiatr., 135, 1321–3324.PubMedGoogle Scholar
  28. Gardos G. and Cole J. O. (1980) Problems in assessment of tardive dyskinesia, in Tardive Dyskinesia Research and Treatment (Farm W. E., Smith R. G, Davis J. M., and Domino E. F., eds.), Spectrum, Jamaica, NY, pp. 201–214.Google Scholar
  29. Gershanik O., Heikkila R. E., and Duvoisin R. C. (1983) Behavioral correlation of dopamine receptor activation. Neural. 33, 1489–1492.Google Scholar
  30. Gianutsos G., Drawbaugh R. B., Hynes M. D., and Dew Lal H. (1974) Behavioral evidence for dopaminergic supersensitivity after chronic haloperidol. Life Sci. 141, 887–898.CrossRefGoogle Scholar
  31. Glassman R. B. and Glassman N. H. (1980) Oral dyskinesia in brain-damaged rats following brain lesions and neuroleptic drug administration. Psychopharmacology 77, 134–139.Google Scholar
  32. Gunne L. M. and Barany S. (1976) Haloperidol-induced tardive dyskinesia in monkeys. Psychopharmacology 50, 237–240.PubMedCrossRefGoogle Scholar
  33. Gunne L. M., Bachus S. E., and Gale K. (1980) Oral movements induced by interference with nigral GABA neurotransmission: Relationship to tardive dyskinesias. Exp. Neurol. 100, 459–469.CrossRefGoogle Scholar
  34. Gunne L. M., Growdon J., and Glaeser B. (1982) Oral dyskinesia following rat brain lesions and neuroleptic drug administration. Psychophamracology 77, 134–139.CrossRefGoogle Scholar
  35. Gunne L. M. and Haggstrom J. E. (1983) Reduction of nigral glutamic acid decarboxylase in rats with neuroleptic-induced oral dyskinesia. Psychopharmacology 81, 191–194.PubMedCrossRefGoogle Scholar
  36. Gunne L. M., Haggstrom J. E., and Sjoquist B. (1984) Association with persistent neuroleptic-induced dyskinesia of regional changes in brain GABA synthesis. Nature 309, 347–349.PubMedCrossRefGoogle Scholar
  37. Gunne L. M., Andersson U., Bondesson U., and Johansson P. (1986) Spontaneous chewing movements in rats during acute and chronic antipsychotic drug administration. Pharmacol. Biochem. 25, 897–901.CrossRefGoogle Scholar
  38. Hall R. A., Jackson R. B., and Swain J. (1956) Neurotoxic reactions resulting from chlorpromazine administration. J. Am. Med. Assoc. 214–218.Google Scholar
  39. Hall K., Kohler C., and Gariell L. (1985) Some in vitro receptor binding properties of 3H eticlopride, a novel substituted benzamide selective for dopamine D2 receptors in the rat’s brain. Eur. J. Pharmacol. 111, 191–199.PubMedCrossRefGoogle Scholar
  40. Hamblin M. W. and Creese I. (1983) Behavioral and radioligand binding evidence from irreversible dopamine receptor blockade by N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline. Life Sci. 32, 2247–2255.PubMedCrossRefGoogle Scholar
  41. Hanssen T. E., Brown W. L., Wiegel R. M., and Casey D. E. (1988) Risk factors for drug-induced Parkinsonism in tardive dyskinesia patients. J. Clin. Psychiatr. 49, 139–141.Google Scholar
  42. Hess E. J., Battaglia G., Norman A. B., and Creese I. (1987) Differential modification of striatal dopamine receptors and effector moieties by N-ethoxycarbonyl l-Zethoxy-1, Zdihydroquinoline in vivo and in vitro. Mol. Pharmacol. 31, 50–57.PubMedGoogle Scholar
  43. Hyttel J. (1978) Effects of neuroleptics on 3H-haloperidol and 3H-cis-flupenthixol binding and on adenylate cyclase activity in vitro. Life Set. 23, 551–556.CrossRefGoogle Scholar
  44. Hyttel J. (1983) SCH 23390—the first selective dopamine D1 antagonist. Eur. J. Pharmacol. 91, 153–154.PubMedCrossRefGoogle Scholar
  45. Iorio L. G, Barnett A., Leitz P. H., Houser V. P., and Korduba C. A. (1983) SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems. J. Pharmacol. Exp. Ther. 226, 462–468.PubMedGoogle Scholar
  46. Itil T. M., Reisberg B., Hugure M., and Mehta D. (1981) Clinical profiles of tardive dyskinesia. Compr. Psychiatr. 22, 282–290.CrossRefGoogle Scholar
  47. Itoh Y., Beaulieu M., and Kebabian J. W. (1984) The chemical basis for the blockade of the D1 receptor by SCH 23390. Eur. J. Pharmacol. 100, 119–122.PubMedCrossRefGoogle Scholar
  48. Jus A., Jus K., and Fontaine P. (1979) Long-term treatment of tardive dyskinesia. J. Clin. Psychiatr. 40, 72–77.Google Scholar
  49. Kaiser C. (1983) In Stereoisomeric Probes for the Dopamine Reqdors. (Kaiser C., and Kebabian J. W., eds.), American Chemical Society, Washington, DC, pp. 223–250.Google Scholar
  50. Kane J. M. and Smith J. M. (1982) Tardive dyskinesia: prevalence and risk factors 1959-1979. Arch. Gen. Psychiatr. 39, 473–481.PubMedGoogle Scholar
  51. Klawans H. L. (1973) The pharmacology of tardive dyskinesia. Am. J. Psychiatr. 130, 82–86.PubMedGoogle Scholar
  52. Kosgaard S., Gerlach J., and Christensson E. (1985) Behavioral aspects of serotonin dopamine interaction in the monkey. Eur. J. Pharmacol. 118, 245–252.CrossRefGoogle Scholar
  53. Kovacic B. and Domino E. F. (1982) A monkey model of tardive dyskinesia (TD), evidence that reversible TD may turn into irreversible TD. J. Clin. Psychopharmacol. 2, 305–306.PubMedCrossRefGoogle Scholar
  54. Kullenkampf C. and Tarnow G. (1956) Ein Eigentumiiches Syndrom im oralen Bereich bei Megaphenaaplikation. Neruenarzt 27, 178–180.Google Scholar
  55. Liebman J. and Neale R. (1980) Neuroleptic-induced acute dyskinesias in squirrel monkeys. Correlation with propensity to cause extrapyramidal side effects. Psychopharmacology 68, 25–29.PubMedCrossRefGoogle Scholar
  56. Lubin H. and Gerlach J. (1988) Behavioral effects of dopamine D1 and D2 receptor agonists in monkeys previously treated with haloperidol. Eur. J. Pharmacol. 153, 239–245.CrossRefGoogle Scholar
  57. Mao C. C., Chenney L. M, Marco E., Revuetta A., and Costa E. (1977) Turnover times of gamma-aminobutyric acid and acetylcholine in nucleus caudatus, nucleus accumbens, globus pallidus and substantia nigra effects of repeated administration of haloperidol. Brain Res. 132, 375–379.PubMedCrossRefGoogle Scholar
  58. Marsden C. D., Tarsy D, and Baldessarini R. J. (1973) Spontaneous and druginduced movement disorders in psychotic patients, in Psychiatric Aspecfs of Neurologic Disease (Benson D. F. and Blummer D., eds.), Grunne and Stratton, NY, pp. 219–266.Google Scholar
  59. Mashurano M. and Waddington J. L. (1986) Stereotyped behavior in response to the selective D2 dopamine receptor agonist RU 24213 is enhanced by pretreatment with selective D1 agonists SKF 38393. Neuropharmacology 25, 947–950.PubMedCrossRefGoogle Scholar
  60. Meller E., Bohmaker K., Goldstein M, and Friedhoff A. J. (1985) Inactivation of D1 and D2 dopamine receptors by N-ethoxycarbonyl-2-ethoxy-1,2dihydroquinoIine in vivo: Selective protection by neuroleptics. J Pharmacol. Exp Ther. 233, 656–662.PubMedGoogle Scholar
  61. Messiha F. (1980) Biochemical studies after chronic administration of neuroleptics to monkeys, in Tardive Dyskinesiu: Research and Treatment (Fann W. E, Smith R. C., Davis J. M., and Domino E. F., eds.), Spectrum, NY, pp. 13–25.Google Scholar
  62. Meller P. and Seeman P. (1977) Brain neurotransmitter receptor after long-term haloperidol. Life Sci. 21, 1751–1758.CrossRefGoogle Scholar
  63. Murray A. M. and Waddington J. L. (1989) Induction of grooming and vacuous chewing by a series of selective D1 dopamine receptor agonists: Two directions of D1: D2 interaction. Eur. J Pharmucol. 160, 377–384.CrossRefGoogle Scholar
  64. Onali P., Olianas M. C, and Gessa G. L. (1984) Selective blockade of dopamine D1 receptors by SCH 23390 discloses striatal dopamine D2 receptors mediating the inhibition of adenylate cyclase in rats. Eur. J Pharmacol. 99, 127–128.PubMedCrossRefGoogle Scholar
  65. Porsolt R. D. and Jalfre M. (1981) Neuroleptic-induced acute dyskinesias in rhesus monkeys. Psychopharmacology 75, 16–21.PubMedCrossRefGoogle Scholar
  66. Rosengarten H, Schweitzer J. W., and Friedhoff A. J. (1983) Induction of oral dyskinesia in naive rats by D1 stimulation. Life Sci. 33, 2479–2482.PubMedCrossRefGoogle Scholar
  67. Rosengarten H., Schweitzer J. W., and Friedhoff A. J. (1986) Selective dopamine D2 receptor reduction enhances a D1 mediated oral dyskinesia in rats. Life Sci. 39, 29–35.PubMedCrossRefGoogle Scholar
  68. Rosengarten H., Schweitzer J. W., and Friedhoff A. J. (1987) Prolonged fiuphenazine decanoate treatment augments oral movements in rats: Mediation by D1 receptor. Sixth Int. Catechofumine Symposium Abstracts, p. 14.Google Scholar
  69. Rosengarten H., Schweitzer J. W., and Friedhoff A. J. (1989) A full repetitive jaw movement response after 70% depletion of caudate D1 receptors Pharmacol. Biochem. Behav. 34, 895–897.PubMedCrossRefGoogle Scholar
  70. Salama A. I. and Saller C. F. (1986) Functional interactive effects of D1 and D2 dopamine receptor blockade. In Neurobiology of Central D1 Dopamine Receptors. Adv. Exp. Med. Biol. 204, 137–140.Google Scholar
  71. Saller C. F. and Salama A. I. (1985) Dopamine receptor subtypes: in vivo biochemical evidence for functional interaction. Eur. J. Pharmacol 109, 297–300.PubMedCrossRefGoogle Scholar
  72. Seeman P. (1980) Brain dopamine receptors. Pharmacol. Rev. 32, 229–313.PubMedGoogle Scholar
  73. Seeman M. V. (1981) Tardive dyskinesia: Two-year recovery. Compr. Psychiatr. 22, 189–192.CrossRefGoogle Scholar
  74. Seeman P. and Grigoriadis D. (1987) Dopamine receptors in brain and periphery. Neurochem. Int. 10, 1–25.PubMedCrossRefGoogle Scholar
  75. Sedvall G., Farde L., and Hall H. (1988) D1 and D2 dopamine receptors in the human brain as studied by in vitro analysis and PET, in Central and Peripheral Dopamine Receptors. Biochemistry and Pharmacology (Spano P. P., Biggie G., Toffano G, and Gessa G. L., eds.), Liviana, pp. 81–86.Google Scholar
  76. Scheel-Kruger J. and Arnt J. (1985) New aspects on the role of dopamine, acetylcholine and G ABA in the development of tardive dyskinesia, in Dyskinesia Research and Treatment. Psychopharmacology 2 (Suppl.), Springer Verlag, Berlin, Heidelberg, pp. 45–56.Google Scholar
  77. Schoeneker M. (1957) Ein Eigentumlichen syndrome in oralen Bereich bei Megaphen Applikation. Nervenarzt 28 35–37.Google Scholar
  78. Sibley D. R., Leff S. E., and Creese I. (1982) Interaction of novel dopaminergic Iigands with D1 and D2 dopamine receptors. Life Sci. 31, 637–645.PubMedCrossRefGoogle Scholar
  79. Sigwald J., Bouttier D., and Raymondeaud C. (1959) Quatre cas de dyskinesie faciobucco-Iinguo-masticatrice a I’evolution prolongee secondaire a un traitemant par les neuroleptiques. Rev. Neurol. 100, 751–755.PubMedGoogle Scholar
  80. Smith J. M. and Baldessarini R. J. (1980) Change in prevalence severity and recovery of tardive dyskinesia with age. Arch. Gen. Psychiatr. 37, 1368–1373.PubMedGoogle Scholar
  81. Stoof J. C. and Kebabian J. W. (1981) Opposing roles for the D1 and D2 dopamine receptors in efflux of cyclic AMP from rat striatum. Nature 294, 366–368.PubMedCrossRefGoogle Scholar
  82. Tarsy D. and Baldessarini R. J. (1977) The pathophysiologic basis of tardive dyskinesia. Biol. Psychiatr. 12, 431–449.Google Scholar
  83. Toenniesen L. M., Casey D. E., and McFarland, B. H. (1985) Tardive dyskinesia in the aged: duration and treatment relationship. Arch. Gen. Psychiatr. 42, 278–284.Google Scholar
  84. Tsuruta K., Frey E. A., Grewe C. W., Cote T. E., Eskay R. L., and Kebabian J. W. (1981) Evidence that LY141865 specifically stimulates the D2 dopamine receptor. Nature 292, 463–465.PubMedCrossRefGoogle Scholar
  85. Uhrband L. and Faurbye A. (1960) Reversible and irreversible dyskinesia after treatment with perphanazine, chlorpromazine, reserpine and electroconvulsive therapy. Psychopharmacology 1, 408–418.CrossRefGoogle Scholar
  86. Waddington J. L., Molloy A. G., Boyle K. M., and Youssef H. A. (1986) Spontaneous and drug-induced dyskinesias in rodents in relation to aging and long-term neuroleptic treatment: Relationship to tardive dyskinesia, in Biol. Psych., (Shagass C., et al., eds.) Elsevier, NY, pp. 1151–1153.Google Scholar
  87. Waddington J. L. and Gamble S. L. (1980) Neuroleptic treatment for a substantial proportion of adult life: Behavioral sequelae of 9 months haloperidol administration. Eur. J. Phurmucol, 67, 363–364.CrossRefGoogle Scholar
  88. Waddington J. L., Cross A. J., Gamble S. J., and Bourne R. C. (1983) Spontaneous orofacial dyskinesia and dopaminergic function in rats after 6 months of neuroleptic treatment. Science 220, 530–532.PubMedCrossRefGoogle Scholar
  89. Waddington J. L. and Gamble S. J. (1980) Emergency of vacuous chewing during 6 months continuous treatment with fluphenazine decanotate. Eur. J. Pharmacol. 68, 387–388.PubMedCrossRefGoogle Scholar
  90. Wegner J. T. and Kane J. M. (1982) Follow-up study on the reversibility of tardive dyskinesia. Amer. J. Psych. 139, 368–369.Google Scholar
  91. Weiss B., Santelli S., and Lusink G. (1977) Movement disorders induced in monkeys by &tonic haloperidol treatment. Psychoyhannacology 53, 289–293.CrossRefGoogle Scholar
  92. White F. J, (1987) D1 receptor stimulation enables the inhibition of nucleus accumbens neurones by D2 receptor agonist. Eur. J. Pharmacol. 135, 101–105.PubMedCrossRefGoogle Scholar
  93. White P. Y. and Wang R. Y. (1986) Electrophysiological evidence for the existence of both D1 and D2 dopamine receptors in rat nucleus accumbens. J. Neurosci. 6, 274–280.PubMedGoogle Scholar

Copyright information

© The Humana Press Inc. 1991

Authors and Affiliations

  • Helen Rosengarten
    • 1
  • Jack W. Schweitzer
    • 1
  • Arnold J. Friedhoff
    • 1
  1. 1.Department of PsychiatryNew York University School of MedicineNew York

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