A Computerized Methodology for the Study of Neuroleptic-Induced Oral Dyskinesias

  • Gaylord Ellison
  • Ronald E. See
Part of the Neuromethods book series (NM, volume 18)


Although there is a dramatic need for animal models related to schizophrenic symptomatology, the literature has been disappointing in this regard. This is also true for models of the side effects of antipsychotic drugs, particularly with regard to rodent models. Considerable controversy exists as to whether the oral movements induced by antipsychotics in rodents represent an acute-dystonia-like effect or a tardive dyskinesialike effect.


Tardive Dyskinesia Human Observer Drug Withdrawal Neuroleptic Treatment Atypical Neuroleptic 
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. Adler L. A., Angrist B., Reiter S, and Rotrosen J. (1989) Neuroleptic-induced akathisia: A review. Psychopharmacology 97, 1–11.PubMedCrossRefGoogle Scholar
  2. Alpert M., Diamond F., and Friedhoff A. J. (1976) at]Tremographic studies in tardive dyskinesia. Psychopharmacol. Bull. 12(2), 5.Google Scholar
  3. Ayd F. J. (1961) A survey of drug-induced extrapyramidal reactions. JAMA 175, 1054–1060.PubMedGoogle Scholar
  4. Barnes T. R. and Braude W. M. (1985) Akathesia variants and tardive dyskinesia. Arch. Gen. Psychiat. 42, 874–878.PubMedGoogle Scholar
  5. Bedard P., Delean J., Lafleur J., and LarocheIIe L.(1977) Haloperidol-induced dyskinesias in the monkey. J. Can. Sci. 4, 197–201.Google Scholar
  6. Beresford R. and Ward A. (1987) Haloperidol decanoate: A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis. Drugs 33, 31–49.PubMedCrossRefGoogle Scholar
  7. Burke R. E., Fahn S, Jankovic J., Marsden C. D., Lang A. E., Gollomp S., and IIson J. (1982) Tardive dystonia: Late-onset and persistent dystonia caused by antipsychotic drugs. Neurology 32, 1335–1346.PubMedGoogle Scholar
  8. CaIigiuri M., Jeste D., and Harris M. (1989) Instrumental assessment of lingual motor instability in tardive dyskinesia. Neuropsychopharmacology 2, 309–312.CrossRefGoogle Scholar
  9. Casey D. E. (1984) Tardive dyskinesia-animal models. Psychopharmacol. Bull. 20, 376–379.PubMedGoogle Scholar
  10. Casey D. E. (1985a) Tardive dyskinesia: Epidemiologic factors as a guide for prevention and management, in Chronic Treatments in Neuropsychiatry (Kemali D. and Racagni G., eds.), Raven, NY, pp. 15–24.Google Scholar
  11. Casey D. E. (1985b) Tardive dyskinesia: Reversible and irreversible, in Dyskinesia—Research and Treatment (Casey D. E., Chase T. N., Christensen A. V, and Gerlach J., eds.), Springer, Heidelberg, pp. 88–97.Google Scholar
  12. Chien C., Jung K., and Ross-Townsend A. (1980) Methodological approach to the measurement of tardive dyskinesia: Piezoelectric recording and concurrent validity test on give give clinical rating scales. Tardive Dyskinesia: Research and Treatmentl (Prann W., Smith R, Davis J., and Domino E., eds.). Spectrum Publications, New York, NY, pp. 233–241.Google Scholar
  13. Clow A., Jenner I’., and Marsden C. D. (1979) Changes in dopamine-medi-ated behaviour during one year’s neuroleptic administration. Eur. J; Pharmacol. 57, 365–375.PubMedCrossRefGoogle Scholar
  14. Clow A., Theodorou A., Jenner P., and Marsden C. D. (1980) Cerebral do-pamine function in rats following withdrawal from one year of continuous neuroleptic administration. Eur. J. Pharmucol. 63, 145–157.CrossRefGoogle Scholar
  15. Crane G. E. (1973) Persistent dyskinesia. Br. J. Psychiat 122, 395–405.CrossRefGoogle Scholar
  16. Creese I.(1983) Receptor interactions of neuroleptics, in Neuroleptics: Neurochemical., Behavioral, and Clinical Perspectives (Coyle J. T. and Enna S. J., eds.), Raven, NY, pp. 183–223.Google Scholar
  17. Csernansky J. G., Grabowski K, Cervantes J., Kaplan J., and Yesavage J. A. (1981) Fluphenazine decanoate and tardive dyskinesia: A possible association. Am. J. Psychiat. 138(10), 1362–1365.PubMedGoogle Scholar
  18. Deneau G. and Crane G. (1969) Dyskinesia in rhesus monkeys tested with high doses of chlorpromazine, in Psychotropic Drugs and Dysfunction of the Basal Ganglia (Crane G. and Gardner R., eds.), US Public Health Service, Washington, DC, pp. 12–14.Google Scholar
  19. Domino E. and Kovacic B. (1983) Monkey models of tardive dyskinesia. Mod. Probl. PharmacoPsychiat. 21, 21–33.Google Scholar
  20. Domino E. F. (1985) Induction of tardive dyskinesia in Cebus apella and macaca speciosa monkeys: A review, in Dyskinesia—Research and Treatment (Casey D. E, Chase T. N., Christensen A. V., and Gerlach J., eds.), Springer, Heidelberg, pp. 217–223.Google Scholar
  21. Ellison G. and Morris W. (1981) Opposed stages of continuous amphetamine administration: Parallel alterations in motor stereotypies and in vivo spiroperidol accumulation. Eur. J. Pharmacol. 74, 207–214.PubMedCrossRefGoogle Scholar
  22. Ellison G. D. 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
  23. Ellison G., Staugaitis S., and Crane P. (1981) A silicone delivery system for producing binge and continuous ethanol intoxication in rats. Pharmacol. Biochem. Behav. 14, 207–211.PubMedCrossRefGoogle Scholar
  24. Ellison G., Eison M., Huberman H., and Daniel P. (1978) Structural and biochemical alterations in dopaminergic innervation of the caudate nucleus following continuous amphetamine administration. Science 201, 276–278.PubMedCrossRefGoogle Scholar
  25. Ellison G. D., See R. E., Levin E. D, and Kinney J. (1987) Tremorous mouth movements in rats administered chronic neuroleptics. Psychoyharmacology 92, 122–126.CrossRefGoogle Scholar
  26. Fann W. E., Stafford J., Malone R., Frost J., and Richman B. (1977) Clinical research techniques in tardive dyskinesia. Am. J. Psychiat. 134, 759.PubMedGoogle Scholar
  27. Gardos G., Cole J. 0, and Tarsy D. (1978) Withdrawal syndromes associated with antipsycholic drugs. Am.1. Psychiat 135, 1321–1324.Google Scholar
  28. Gardos G., Cole J. O., Salomon M, and Schnielbolk S. (1987) Clinical forms of severe tardive dyskinesia. Am. J. Psychiat. 144, 895–902.PubMedGoogle Scholar
  29. Gerlach J. and Casey D. E. (1984) Sulpiride in tardive dyskinesia. Acta Psychiatr. Stand. (Suppl.) 311, 93–102.CrossRefGoogle Scholar
  30. Gerlach J., Koppelhus P., Helweg E, and Monrad A. V. (1974) Clozapine and haloperidol in single-blind cross-over trial: Therapeutic and biochemical aspects in the treatment of schizophrenia. Acta Psychiatr. Stand. 50, 410–424.CrossRefGoogle Scholar
  31. Glassman R. and Glassman H. (1980) Oral dyskinesias in brain-damaged rats withdrawn from a neuroleptic: Implications for models of tardive dyskinesia. Psychopharmacology 69, 19–25.PubMedCrossRefGoogle Scholar
  32. Goldman M. B. and Luchins D. J. (1984) Intermittent neuroleptic therapy and tardive dyskinegia: A literature review. Hosp. Comm. Psychiat. 35, 1215–1219.Google Scholar
  33. Gunne L. M. and Barany S. (1976) Haloperidol-induced tardive dyskinesia in monkeys. Psychopharmacology 50, 237–240.PubMedCrossRefGoogle Scholar
  34. 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
  35. Gunne L. M., Haggstrom J.E., and Syoquist B. (1984) Association with persistent neuroleptic-induced dyskinesia of regional changes in brain GABA synthesis. Nature 309(24), 347–349.PubMedCrossRefGoogle Scholar
  36. Gunne L. M., Andersson U, Bondesson U., and Johansson P. (1986) Spontaneous chewing movements in rats during acute and chronic anti-psychotic drug administration. Pharmacol. Biochem. Behav. 25, 897–901.PubMedCrossRefGoogle Scholar
  37. Guy W., Ban T. A., and Wilson W. H. (1985) An international survey of tardive dyskinesia. Prog. Neuropsychopharmacol. Biol. Psychiat. 9, 401–405.CrossRefGoogle Scholar
  38. Hall H., Kohler C., Gawell L., Farde L., and Sedvall G. (1988) Raclopride, a new selective ligand for the dopamine-D2 receptors. Prog. Neuroysycoyharmacol. Biol. Psychiat, 12, 559–568.CrossRefGoogle Scholar
  39. Iversen S. D., Howells R. B., and Hughes R. P. (1980) Behavioral consequences of long-term treatment with neuroleptic drugs. Adv. Biochem. Psychoyharmacol. 24, 305–313.Google Scholar
  40. Jeste D. V., Lohr J. B., Clark K, and Wyatt R. J. W. (1988) Pharmacological treatments of tardive dyskinesia in the 1980s. J Clin. Psychopharmacol. 8, 385–485.CrossRefGoogle Scholar
  41. Jeste D. V. and Wyatt R. J. W. (1982) Therapeutic strategies against tardive dyskinesia: Two decades of experience. Arch. Gen. Psychiat. 39, 803–816.PubMedGoogle Scholar
  42. Johansson P. (1989) Characterization and application of animal models for tardive dyskinesia. Uppsala, Sweden, Acta Univ. Uysaliensis 222, pp. 1–46.Google Scholar
  43. Johansson P., Casey D. E., and Gunne L. M. (1986) Dose-dependent increases in rat spontaneaus chewing rates during long-term administration of haloperidol but not clozapine. Psychopharmacol. Bull. 22, 1017–1019.Google Scholar
  44. Kane J. M. and Smith J. M. (1982) Tardive dyskinesia: Prevalence and risk factors, 1959-1979. Arch. Gen. Psychiat. 39, 473–481.PubMedGoogle Scholar
  45. Klawans H. L. (1973) The pharmacology of tardive dyskinesias. Am. J Psychiat. 130, 82–86.PubMedGoogle Scholar
  46. Kovacic B. and Domino E. F. (1984) Fluphenazine-induced acute and tardive dyskinesia in monkeys. Psychopharmacology 84, 310–314.PubMedCrossRefGoogle Scholar
  47. Kovacic B., Ruffmg D., and Stanley M. (1986) Effect of neuroleptics and of potential new antipsychotic agents (MJ13859-1 and MJ13980-1) on a monkey model of tardive dyskinesia. J. Neural. Transm. 165, 39–49.CrossRefGoogle Scholar
  48. Lees A. J. (1985) Tics and Related Disorders (Churchill Livingstone, Eding-burgh), pp. 191–234.Google Scholar
  49. Levin E. D., Galen D., and Ellison G. D. (1987) Chronic haloperidol effects on radial-arm maze performance and oral movements in rats. Pharmacol. Biochem. Behav. 26, 145.CrossRefGoogle Scholar
  50. Levy A. D., See R. E., Levin E. D., and Ellison G. D. (1987) Neuroleptic-induced oral movements in rats: Methodological issues. Life Sci. 41, 1499–1506.PubMedCrossRefGoogle Scholar
  51. 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
  52. Lindstrom L. H. (1988) The effect of long-term treatment with clozapine in schizophrenia: A retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr. Scand. 77, 524–529.PubMedCrossRefGoogle Scholar
  53. McGeer P. L., Boulding J. E., Gibson W. C., and Foulkes R. G. (1961) Druginduced extrapyramidal reactions.J. Am. Med. Assoc. 177, 665–670.Google Scholar
  54. McKinney W. T., Moran E. C., Kraemer G. W, and Prange A. J. (1980) Longterm chlorpromazine in rhesus monkeys: Production of dyskinesias and changes in social behavior. Psychopharmacology 72, 35–39.PubMedCrossRefGoogle Scholar
  55. Marsden C. D. and Jenner P. (1980) The pathophysiology of extrapyramidal side effects of neuroleptic drugs. Psychol. Med. 10, 55–72.PubMedCrossRefGoogle Scholar
  56. Mithani S., Atmadja S., Baimbridge K. G., and Fibiger H. C. (1987) Neuroleptic-induced oral dyskinesias, effects of progabide and lack of corre-lation with regional changes in glutamic acid decarboxylase and cho-line acetyltransferase activities. Psychopharmacology 93, 94–100.PubMedCrossRefGoogle Scholar
  57. Moore D. C. and Bowers M. B. (1980) Identification for a subgroup of tardive dyskinesia patients by pharmacologic probes. Am. J. Psychiat. 137, 1202–1205.PubMedGoogle Scholar
  58. Neale R., Gerhardt S., and Liebman J. M. (1984) Effects of dopamine agonists, catecholamine depletors, and cholinergic and GABAergic drugs on acute dyskinesias in squirrel monkeys. Psychopharmacology 82, 20–26.PubMedCrossRefGoogle Scholar
  59. Niemegeers C. J. E. and Janssen P. A. J. (1979) A systematic review of the pharmacological activities of dopamine antagonists. Life Sci. 24, 2201–2216.PubMedCrossRefGoogle Scholar
  60. Owen F., Cross A. J., Waddington J. L., Poulter M., Gamble S. J., and Crow T. J. (1980) Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months haloperidol administration. Life Sci. 26(l), 55–59.PubMedGoogle Scholar
  61. Pi E. H. and Simpson G. M. (1983) Atypical neuroleptics: Clozapine and the benzamides in the prevention and treatment of tardive dyskinesia. Mod. Probl. PharmacoPsychiat. 21, 80–86.Google Scholar
  62. Post R. M. (1980) Intermittent versus continuous stimulation: Effect of time interval on the development of sensitization or tolerance. Life Sci. 26, 1275–1282.PubMedCrossRefGoogle Scholar
  63. Potthoff A. U, Ellison G, and Nelson L. (1983) Ethanol intake increases during continuous administration of amphetamine and nicotine, but not several other drugs. Pharmacol. Biochem. Behav. 18, 489–495.PubMedCrossRefGoogle Scholar
  64. Robertson A. and MacDonald C. (1984) Atypical neuroleptics clozapine and thioridazine enhance amphetamine-induced stereotypy. Pharmacol. Biochem. Behav. 21, 97–101.PubMedCrossRefGoogle Scholar
  65. Rodriguez L. A., Moss D. E., Reyes E., and Camarena M. L. (1986) Perioral behaviors induced by cholinesterase inhibitors: A controversial animal model. Pharmacol. Biochem. Behav. 25, 1217–1221.PubMedCrossRefGoogle Scholar
  66. Rondot P. and Bathien N. (1986) Movement disorders in patients with coexistent neuroleptic-induced tremor and tardive dyskinesia: EMG and pharmacologic study. Adv. Neural. 45, 361.Google Scholar
  67. Rosengarten H., Schweitzer J. W, and Priedhoff A. J. (1983) Induction of oral dyskinesias in naive rats by Dl stimulation. Life Sci. 33, 2479–2482.PubMedCrossRefGoogle Scholar
  68. Rosengarten H., Schweitzer J. W, and Friedhoff A. J. (1986) Selective dopamine D2 receptor reduction enhances a Dl mediated oral dyskinesia in rats. Life Sci. 39, 29–35.PubMedCrossRefGoogle Scholar
  69. Rupniak N. M. J., Jenner P., and Marsden C. D. (1983) Cholinegic manipulation of perioral behaviour induced by chronic neuroleptic administration to rats. Psychopharmacology 79, 226–230.PubMedCrossRefGoogle Scholar
  70. Rupniak N. M. J., Jenner P., and Marsden C. D. (1985) Pharmacological characterisation of spontaneous or drug-associated purposeless chewing movements in rats. Psychopharmacology 85, 71–79.PubMedCrossRefGoogle Scholar
  71. Rupniak N. M. J., Jenner P., and Marsden C. D. (1986) Acute dystonia induced by neuroleptic drug. Psychophurmacology 88, 403–419.Google Scholar
  72. Rupniak N. M. J., Mann S., Hall M. D., Fleminger S., Kilpatrick G., Jenner P., and Marsden C. D. (1984) Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat. Psychopharmarcology 84, 503.CrossRefGoogle Scholar
  73. Sahakian B. J., Robbins T. W, and Iversen S. D. (1976) Pluphenthixol-induced hyperactivity by chronic dosing in rats. Eur. J. Pharmacol. 37, 169–178.PubMedCrossRefGoogle Scholar
  74. Sant W. W. and Ellison G. (1984) Drug holidays alter onset of oral movements in rats following chronic haloperidol. Bio. Psychiut. 19, 95–99.CrossRefGoogle Scholar
  75. See R. E. and Ellison G. (1990a) Intermittent and continuous haloperidol regimens produce different types of oral dyskinesias in rats. Psychopharmacology 100, 404–412.PubMedCrossRefGoogle Scholar
  76. See R. E. and Ellison G. (1990b) Comparison of chronic administration of haloperidol and the atypical neuroleptics, clozapine and raclopride, in an animal model of tardive dyskinesia. Eur. J. Pharmacol. 181, 175–186.PubMedCrossRefGoogle Scholar
  77. See R. E., Levin E. D., and Ellison G. D. (1988) Characteristics of oral movements in rats during and after chronic haloperidol and fluphenazine administration, Psychopharmacology 94, 421–427.PubMedCrossRefGoogle Scholar
  78. See R., Sant W. W., and Ellison G. (1987) Recording oral activity in rats reveals a long-lasting subsensitivity to haloperidol as a function of duration of previous haloperidol treatment. Pharmucol. Biochem. Behuu. 28, 175–178.CrossRefGoogle Scholar
  79. Stewart B. R., Rupniak N. M. J., Jenner P., and Marsden C. D. (1988) Animal models of neuroleptic-induced acute dystonia, in Advances in Neurology, vol. 50: Dystoniu 2 (Fahn S., Marsden C. D., and Calne D. B., eds.), Raven, New York., pp. 343–359.Google Scholar
  80. Tamminga C. A. and Gerlach J. (1987) New neuroleptics and experimental antipsychotics in schizophrenia, in Psychopharmacology—The Third Generation of Progress (Meltzer H. Y, ed.), Raven, NY, pp. 1129–1140.Google Scholar
  81. Tarsy D. and Baldessarini R. (1974) Behavioral supersensitivity to apomorphine following chronic treatment with drugs which interfere with synaptic function of catecholamines. Neuropharmacology 13, 927–928.PubMedCrossRefGoogle Scholar
  82. Tryon W. W. and Pologe B. (1987) Accelerometric assessment of tardive dyskinesia. Am. J. Psychiat. 144, 1584–1587.PubMedGoogle Scholar
  83. Waddington J. L, Cross A. J., Gamble S. J., and Bourne R. C. (1983) Spontaneous orofacial dysldnesia and dopaminergic function in rats after six months of neuroleptic treatment. Science 220, 530–532.PubMedCrossRefGoogle Scholar
  84. Waddington J. L., Youssef H. A., Molloy A. G., O’Boyle K. M., and Pugh M. T. (1985) Association of intellectual impairment, negative symptoral movements, and aging with tardive dyskinesia: Clinical and animal studies. J. Clin. Psychiat. 46, 29–33.Google Scholar
  85. Weiss B. and Santelli S. (1978) Dyskinesias evoked in monkeys by weekly administration of haloperidol. Science 200, 799–801.PubMedCrossRefGoogle Scholar
  86. Wirshing W. C., Cummings J. L., Lathers P., and Engel J. (1989) The machine measured characteristics of tardive dyskinesia. Schizoyhr. Res. 2, 240.CrossRefGoogle Scholar

Copyright information

© The Humana Press Inc. 1991

Authors and Affiliations

  • Gaylord Ellison
  • Ronald E. See
    • 1
  1. 1.Department of PsychologyUniversity of CaliforniaLos Angeles

Personalised recommendations