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Spontaneous orofacial movements induced in rodents by very long-term neuroleptic drug administration: phenomenology, pathophysiology and putative relationship to tardive dyskinesia

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Abstract

While understanding of the major clinical and ethical issue of tardive dyskinesia would be greatly facilitated by the development of an isomorphic or homologous animal model, particularly in rodents, this has proved to be a highly contentious issue. The literature on orofacial function in rats administered neuroleptic drugs for substantial proportions of their adult lifespan is reviewed. It reveals the emergence of late-onset orofacial movements in a number of studies, but very early-onset movements or no effect in others. Potential explantations for these discrepancies are considered, and ways of resolving such inconsistencies are suggested. The relationship of these various orofacial phenomena to dopaminergic and non-dopaminergic function, and to clinical syndromes, is critically evaluated.

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References

  • Andersson U, Haggstrom J-E, Levin E, Bondersson U, Valverius M, Gunne LM (1989) Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia. Mov Disord 4:37–46

    Google Scholar 

  • Blin J, Baron JC, Cambon H, Bonnet AM, Dubois B, Loc'h C, Maziere B, Agid Y (1989) Striatal dopamine D-2 receptors in tardive dyskinesia: PET study. J Neurol Neurosurg Psychiatry 52:1248–1252

    Google Scholar 

  • Brandon S, McClelland HA, Protheroe C (1971) A study of facial dyskinesia in a mental hospital population. Br J Psychiatry 118:171–184

    Google Scholar 

  • Burke RE, Fahn S, Jankovic J, Marsden CD, Lang AE, Gollomp S, Ilson J (1982) Tardive dystonia: late-onset and persistent dystonia caused by antipsychotic drugs. Neurology 32:1335–1346

    Google Scholar 

  • Casey DE (1985) Tardive dyskinesia: reversible and irreversible. In: Casey DE, Chase TN, Christensen AV, Gerlach J (eds) Dyskinesia: research and treatment. Springer, Berlin Heidelberg New York, pp 88–97

    Google Scholar 

  • Clow A, Jenner P, Marsden CD (1979) Changes in dopamine-mediated behaviour during one year's neuroleptic administration. Eur J Pharmacol 57:365–375

    Google Scholar 

  • Clow A, Theodorou A, Jenner P, Marsden CD (1980) Cerebral dopamine function in rats following withdrawal from one year of continuous neuroleptic administration. Eur J Pharmacol 63:145–157

    Google Scholar 

  • Cross AJ, Crow TJ, Ferrier IN, Johnson JA, Johnstone EC, Owen F, Owens DGC, Poulter M (1985) Chemical and structural changes in the brain in patients with movement disorder. In: Casey DE, Chase TN, Christensen AV, Gerlach J (eds) Dyskinesia: research and treatment. Springer, Berlin Heidelberg New York, pp 104–110

    Google Scholar 

  • Crossman AR (1987) Primate models of dyskinesia. Neuroscience 21:1–40

    Google Scholar 

  • Ellison G, See RE (1989) Rats administered chronic neuroleptics develop oral movements which are similar in form to those in humans with tardive dyskinesia. Psychopharmacology 98:564–566

    Google Scholar 

  • Ellison G, See R, Levin E, Kinney J (1987) Tremorous mouth movements in rats administered chronic neuroleptics. Psychopharmacology 92:122–126

    Google Scholar 

  • Ellison G, Johansson P, Levin E, See R, Gunne L (1988) Chronic neuroleptics alter the effects of the D-1 agonist SK&F 38393 and the D-2 agonist LY 171555 on oral movements in rats. Psychopharmacology 96:253–257

    Google Scholar 

  • Fibiger HC, Lloyd KG (1984) Neurobiological substrates of tardive dyskinesia: the GABA hypothesis. Trends Neurosci 7:462–464

    Google Scholar 

  • Gardos G, Cole JO, Rapkin RM, LaBrie RA, Baquelod E, Moore P, Sovner R, Doyle J (1984) Anticholinergic challenge and neuroleptic withdrawal: changes in dyskinesia and symptom measures. Arch Gen Psychiatry 41:1030–1035

    Google Scholar 

  • Gerlach J, Casey DE (1988) Tardive dyskinesia. Acta Psychiatr Scand 77:369–378

    Google Scholar 

  • Glassman RB, Glassman HN (1980) Oral dyskinesia in braindamaged rats withdrawn from a neuroleptic: implications for models of tardive dyskinesia. Psychopharmacology 69:19–25

    Google Scholar 

  • Glenthoj B, Hemmingsen R (1989) Intermittent neuroleptic treatment induces long-lasting abnormal mouthing in the rat. Eur J Pharmacol 164:393–396

    Google Scholar 

  • Gunne LM, Haggstrom J-E (1983) Reduction in nigral glutamic acid decarboxylase in rats with neuroleptic-induced oral dyskinesia. Psychopharmacology 81:191–194

    Google Scholar 

  • Gunne LM, Growdon J, Glaeser B (1982) Oral dyskinesia in rats following brain lesions and neuroleptic drug administration. Psychopharmacology 77:134–139

    Google Scholar 

  • Gunne LM, Haggstrom J-E, Sjoquist B (1984) Association with persistent neuroleptic-induced dyskinesia of regional changes in brain GABA synthesis. Nature 309:347–349

    Google Scholar 

  • Gunne LM, Andersson U, Bondesson U, Johansson P (1986) Spontaneous chewing movements in rats during acute and chronic antipsychotic drug administration. Pharmacol Biochem Behav 25:897–901

    Google Scholar 

  • Guy W (1976) Abnormal involuntary movement scale. In: Guy W (ed) ECDEU assessment manual. US Department of Health and Human Services, Rockville, pp 534–537

    Google Scholar 

  • Iversen SD, Howells RB, Hughes RP (1980) Behavioural consequences of long-term treatment with neuroleptic drugs. Adv Biochem Psychopharmacol 24:305–313

    Google Scholar 

  • Jenner P, Marsden CD (1986) Is the dopamine hypothesis of tardive dyskinesia completely wrong? Trends Neurosci 9:259

    Google Scholar 

  • Jenner P, Marsden CD (1987) Chronic pharmacological manipulation of dopamine receptors in brain. Neuropharmacology 26:931–940

    Google Scholar 

  • Jeste DV, Wyatt RJ (1982a) Understanding and treating tardive dyskinesia. Guilford Press, New York

    Google Scholar 

  • Jeste DV, Wyatt RJ (1982b) Therapeutic strategies against tardive dyskinesia. Arch Gen Psychiatry 39:803–816

    Google Scholar 

  • Johansson P, Casey DE, Gunne LM (1986) Dose-dependent increases in rat spontaneous chewing rates during long-term administration of haloperidol but not clozapine. Psychopharmacol Bull 22:1017–1019

    Google Scholar 

  • Kane JM, Smith JM (1982) Tardive dyskinesia. Arch Gen Psychiatry 39:473–481

    Google Scholar 

  • Kane JM, Woerner M, Lieberman J (1985) Tardive dyskinesia: prevalence, incidence and risk factors. In: Casey DE, Chase TN, Christensen AV, Gerlach J (eds) Dyskinesia: research and treatment. Springer, Berlin Heidelberg New York, pp 72–78

    Google Scholar 

  • Kane JM, Woerner M, Borenstein M, Wegner J, Lieberman J (1986) Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull 22:254–258

    Google Scholar 

  • Kane JM, Honigfeld G, Singer J, Meltzer HY (1988) Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

    Google Scholar 

  • Klawans HL, Rubovits R (1972) An experimental model of tardive dyskinesia. J Neural Transm 33:235–246

    Google Scholar 

  • Klawans HL, Tanner CM, Barr A (1984) The reversibility of “permanent” tardive dyskinesia. Clin Neuropharmacol 7:153–159

    Google Scholar 

  • Klawans HL, Carvey P, Tanner CM, Goetz CG (1985) The pathophysiology of tardive dyskinesia. J Clin Psychiatry 46 [4, Sec 2]:38–41

    Google Scholar 

  • Kovacic B, Domino EF (1984) Fluphenazine-induced acute and tardive dyskinesias in monkeys. Psychopharmacology 84:310–314

    Google Scholar 

  • Kornhuber J, Riederer P, Reynolds GP, Beckmann H, Jellinger K, Gabriel E (1989)3H-spiperone binding sites in post-mortem brains from schizophrenic patients: relationship to neuroleptic drug treatment, abnormal movements and positive symptoms. J Neural Transm 75:1–10

    Google Scholar 

  • Levin ED, Galen DM, Ellison GD (1987) Chronic haloperidol effects on oral movements and radial-arm maze performance in rats. Pharmacol Biochem Behav 26:1–6

    Google Scholar 

  • Levy AD, Ellison GD (1987) Interaction between chronic amphetamine and neuroleptic treatments on oral behaviour in rats. Psychopharmacology 93:218–222

    Google Scholar 

  • Levy AD, See RD, Levin ED, Ellison GD (1987) Neuroleptic-induced oral movements in rats: methodological issues. Life Sci 41:1499–1506

    Google Scholar 

  • Lieberman J, Pollack S, Lesser M, Kane JM (1988) Pharmacologic characterisation of tardive dyskinesia. J Clin Psychopharmacol 8:254–260

    Google Scholar 

  • Losonczy MF, Davidson M, Lobel D, Fowler J, Crispman D, Wolf AP, Davis KL (1989) Methodological issues in PET scan evaluation of dopamine supersensitivity in tardive dyskinesia. Schizophr Res 2:112

    Google Scholar 

  • Mithani S, Atmadja S, Baimbridge KG, Fibiger HC (1987) Neuroleptic-induced oral dyskinesias: effects of progabide and lack of correlation with regional changes in glutamic acid decarboxylase and choline acetyltransferase activities. Psychopharmacology 93:94–100

    Google Scholar 

  • Muller P, Seeman P (1978) Dopaminergic supersensitivity after neuroleptics: time course and specificity. Psychopharmacology 60:1–11

    Google Scholar 

  • Owens DGC (1985) Involuntary disorders of movement in chronic schizophrenia: the role of the illness and its treatment. In: Casey DE, Chase TN, Christensen AV, Gerlach J (eds) Dyskinesia: research and treatment. Springer, Berlin Heidelberg New York, pp 79–87

    Google Scholar 

  • Owens DGC, Johnstone EC, Frith CD (1982) Spontaneous involuntary disorders of movement: their prevalence, severity and distribution in chronic schizophrenics with and without treatment with neuroleptics. Arch Gen Psychiatry 39:452–461

    Google Scholar 

  • Perry TL, Hansen S, Jones K (1989) Schizophrenia, tardive dyskinesia and brain GABA. Biol Psychiatry 25:200–206

    Google Scholar 

  • Reynolds GP, McCall C, Mackay A (1989) Post-mortem neurochemical studies of tardive dyskinesia. Schizophr Res 2:106

    Google Scholar 

  • Rodriguez LA, Moss DE, Reyes E, Camarena ML (1986) Perioral behaviours induced by cholinesterase inhibitors: a controversial animal model. Pharmacol Biochem Behav 25:1217–1221

    Google Scholar 

  • Rosengarten H, Schweitzer JW, Friedhoff AJ (1983) Induction of oral dyskinesias in naive rats by D-1 stimulation. Life Sci 33:2479–2482

    Google Scholar 

  • Rosengarten H, Schweitzer JW, Egawa M, Friedhoff AJ (1988) Diminished D-2 dopamine receptor function and the emergence of repetitive jaw movements. In: Goldstein M, Fuxe K, Tabachnick I (eds) Central D-1 dopamine receptors. Plenum Press, New York, pp 159–167

    Google Scholar 

  • Rupniak NMJ, Jenner P, Marsden CD (1983a) The effect of chronic neuroleptic administration on cerebral dopamine receptor function. Life Sci 32:2289–2311

    Google Scholar 

  • Rupniak NMJ, Jenner P, Marsden CD (1983b) Cholinergic manipulation of perioral behaviour induced by chronic neuroleptic administration to rats. Psychopharmacology 79:226–230

    Google Scholar 

  • Rupniak NMJ, Mann S, Hall MD, Fleminger S, Kilpatrick G, Jenner P, Marsden CD (1984) Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat. Psychopharmacology 84:503–511

    Google Scholar 

  • Rupniak NMJ, Hall MD, Mann S, Fleminger S, Kilpatrick G, Jenner P, Marsden CD (1985a) Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat. Biochem Pharmacol 34:2755–2763

    Google Scholar 

  • Rupniak NMJ, Jenner P, Marsden CD (1985b) Pharmacological characterisation of spontaneous or drug-associated purposeless chewing movements in rats. Psychopharmacology 85:71–79

    Google Scholar 

  • Rupniak NMJ, Jenner P, Marsden CD (1986) Acute dystonia induced by neuroleptic drugs. Psychopharmacology 88:403–419

    Google Scholar 

  • Sant WW, Ellison G (1984) Drug holidays alter onset of oral movements in rats following chronic haloperidol. Biol Psychiatry 19:95–99

    Google Scholar 

  • See RE, Levin ED, Ellison GD (1988) Characteristics of oral movements in rats during and after chronic haloperidol and fluphenazine administration. Psychopharmacology 94:421–427

    Google Scholar 

  • See RE, Aravagiri M, Ellison GD (1989) Chronic neuroleptic treatment in rats produces persisting changes in GABAA and dopamine D-2 but not dopamine D-1 receptors. Life Sci 44:229–236

    Google Scholar 

  • Smith JM, Baldessarini RJ (1980) Changes in prevalence, severity and recovery in tardive dyskinesia with age. Arch Gen Psychiatry 37:1368–1373

    Google Scholar 

  • Stahl SM (1986) Tardive dyskinesia: natural history studies assist the pursuit of preventive therapies. Psychol Med 16:491–494

    Google Scholar 

  • Stone RK, Alvarez WF, May JE (1988) Dyskinesia, antipsychotic drug exposure and risk factors in a developmentally-disabled population. Pharmacol Biochem Behav 29:45–51

    Google Scholar 

  • Thaker GK, Tamminga CA, Alphs LD, Lafferman J, Ferraro TN, Hare TA (1987) Brain gamma-aminobutyric acid abnormality in tardive dyskinesia. Arch Gen Psychiatry 44:522–529

    Google Scholar 

  • Toenniessen LM, Casey DE, McFarland BH (1985) Tardive dyskinesia in the aged: duration of treatment relationships. Arch Gen Psychiatry 42:278–284

    Google Scholar 

  • Waddington JL (1984) Tardive dyskinesia: a critical re-evaluation of the causal role of neuroleptics and of the dopamine receptor supersensitivity hypothesis. In: Callaghan N, Galvin R (eds) Recent research in neurology. Pitman, London, pp 34–48

    Google Scholar 

  • Waddington JL (1986) Is the dopamine hypothesis of tardive dyskinesia completely wrong? Trends Neurosci 9:260–261

    Google Scholar 

  • Waddington JL (1987) Tardive dyskinesia in schizophrenia and other disorders: associations with ageing, cognitive dysfunction and structural brain pathology in relation to neuroleptic exposure. Hum Psychopharmacol 2:11–22

    Google Scholar 

  • Waddington JL (1989) Schizophrenia, affective psychoses and other disorders treated with neuroleptic drugs: the enigma of tardive dyskinesia, its neurobiological determinants, and the “conflict of paradigms”. Int Rev Neurobiol 31:297–353

    Google Scholar 

  • Waddington JL, Gamble SJ (1981) Prolonged dopamine receptor blockade in rats after termination of long-term depot fluphenazine. Lancet I:1375–1376

    Google Scholar 

  • Waddington JL, Molloy AG (1986) Duration of treatment relationships for involuntary movements (tardive dyskinesia): concordance between cross-sectional clinical and longitudinal animal studies? Arch Gen Psychiatry 43:191

    Google Scholar 

  • Waddington JL, Molloy AG (1987) The status of late-onset vacuous chewing/perioral movements during long-term neuroleptic treatment in rodents: tardive dyskinesia or dystonia? Psychopharmacology 91:136–137

    Google Scholar 

  • Waddington JL, Youssef HA (1990) The lifetime outcome and involuntary movements of schizophrenia never treated with neuroleptic drugs: four rare cases in Ireland. Br J Psychiatry 156:106–108

    Google Scholar 

  • Waddington JL, Cross AJ, Gamble SJ, Bourne RC (1983a) Spontaneous orofacial dyskinesia and dopaminergic function in rats after 6 months of neuroleptic treatment. Science 220:530–532

    Google Scholar 

  • Waddington JL, Cross AJ, Gamble SJ, Bourne RC (1983b) Dopatmine receptor function and spontaneous orofacial dyskinesia in rats during 6-month neuroleptic treatments. Adv Biochem Psychopharmacol 37:299–308

    Google Scholar 

  • Waddington JL, Youssef HA, Molloy AG, O'Boyle KM, Pugh MT (1985) Association of intellectual impairment, negative symptoms and aging with abnormal, involuntary movements (“tardive” dyskinesia) in schizophrenia: clinical and animal studies. J Clin Psychiatry 46 [4, Sec 2]:29–33

    Google Scholar 

  • Waddington JL, Youssef HA, O'Boyle KM, Molloy AG (1986a) A reappraisal of abnormal involuntary movements (tardive dyskinesia) in schizophrenia and other disorders: animal models and alternative hypotheses. In: Winlow W, Markstein R (eds) The neurobiology of dopamine systems. Manchester University Press, Manchester, pp 266–286

    Google Scholar 

  • Waddington JL, Molloy AG, O'Boyle KM, Youssef HA (1986b) Spontaneous and drug-induced dyskinesias in rodents in relation to ageing and long-term neuroleptic treatment: relationship to tardive dyskinesia. In: Shagass C, Josiassen RC, Bridger W, Weiss K, Stoff D, Simpson G (eds) Biological psychiatry 1985. Elsevier, New York, pp 1151–1153

    Google Scholar 

  • Waddington JL, Youssef HA, Dolphin C, Kinsella A (1987) Cognitive dysfunction, negative symptoms and tardive dyskinesia in schizophrenia: their association in relation to topography of involuntary movements and criterion of their abnormality. Arch Gen Psychiatry 44:907–912

    Google Scholar 

  • Waddington JL, Molloy AG, O'Boyle KM (1988) Behavioural effects of long-term treatment with further typical neuroleptics and selective D-2 dopamine receptor antagonists in young vs aged animals. In: Sandler M, Dahlstrom A, Belmaker R (eds) Progress in catecholamine research. Part B: Central aspects. Liss, New York, pp 43–46

    Google Scholar 

  • Waddington JL, Murray AM, O'Callaghan E, Larkin C (1989) Orofacial dyskinesia: D-1/D-2 dopamine receptors in rodents, and familial/obstetric correlates of tardive dyskinesia in schizophrenia. In: Crossman AR, Sambrook MA (eds) Neural mechanisms in disorders of movement. Libbey, London, pp 359–366

    Google Scholar 

  • Youssef HA, Waddington JL (1988) Involuntary orofacial movements in hospitalised patients with mental handicap or epilepsy: relationship to developmental/intellectual deficit and presence or absence of long-term exposure to neuroleptics. J Neurol Neurosurg Psychiatry 51:863–865

    Google Scholar 

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  1. Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland

    John L. Waddington

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Waddington, J.L. Spontaneous orofacial movements induced in rodents by very long-term neuroleptic drug administration: phenomenology, pathophysiology and putative relationship to tardive dyskinesia. Psychopharmacology 101, 431–447 (1990). https://doi.org/10.1007/BF02244220

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