Skip to main content
Log in

Intermittent and continuous haloperidol regimens produce different types of oral dyskinesias in rats

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rats were administered equivalent doses of haloperidol for either 28 days or 8 months using one of two different drug regimens: intermittent (i.e., weekly injections) or continuously (via drinking water and osmotic minipumps). Oral movements were determined by human observers and by a computerized video analysis system, which determined number and amplitude of jaw openings and closings (computer-scored movelets “CSMs”) as well as the slope (amplitude/duration) and frequency spectrum (fourier transform) of oral activity. The two drug groups developed distinctively different changes over time. Continuous administration resulted in late-onset oral activity changes at 1–3 Hz and withdrawal increases in CSMs, a pattern expected of tardive dyskinesia. Intermittent treatment produced a primed dystonia-like pattern: large amplitude CSMs which had steep onset slopes and a peak energy at 4–7 Hz. These results demonstrate the importance of drug regimen in determining the type of neuroleptic-induced dyskinesias which develop with prolonged neuroleptic treatment in rodents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Alpert M, Diamond F, Friedhoff AJ (1976) Tremographic studies in tardive dyskinesia. Psychopharmacol Bull 12(2):5–7

    Google Scholar 

  • Bannet J, Belmaker RH, Ebstein RP (1980) The effect of drug holidays in an animal model of tardive dyskinesia. Psychopharmacology 69:223–223

    Google Scholar 

  • Belmaker RH, Elami A, Bannet J (1985) Intermittent treatment with droperidol, a short-acting neuroleptic, increases behavioral dopamine receptor sensitivity. In: Casey DE, Chase TN, Christensen AV, Gerlach J (eds) Dyskinesia research and treatment. Springer, Heidelberg, pp 194–199

    Google Scholar 

  • Beresford R, Ward A (1987) Haloperidol decanoate: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis. Drugs 33:31–49

    Google Scholar 

  • Bernardi MM, De Souza H, Neto JP (1981) Effects of single and long-term haloperidol administration on open field behavior of rats. Psychopharmacology 73:171–175

    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 

  • Carey RJ, De Veaugh-Geiss J (1984) Treatment schedule as a determinant of the development of tolerance to haloperidol. Psychopharmacology 82:164–167

    Google Scholar 

  • Casey DE, Gerlach J, Christensson E (1980) Dopamine, acetylcholine, and GABA effects in acute dystonias in primates. Psychopharmacology 70:83–87

    Google Scholar 

  • Crane GE (1973) Persistent dyskinesia. Br J Psychiatry 122:395–405

    Google Scholar 

  • Csernansky JG, Grabowski K, Cervantes J, Kaplan J, Yesavage JA (1981) Fluphenazine decanoate and tardive dyskinesia: a possible association. Am J Psychiatry 138(10):1362–1365

    Google Scholar 

  • Domino EF (1985) Induction of tardive dyskinesia in Cebus apella and macaca speciosa monkeys: a review. In: Casey DE, Chase TN, Christensen AV, Gerlach J (eds) Dyskinesia — research and treatment. Springer, Heidelberg, pp 217–223

    Google Scholar 

  • Domino EF, Kovacic B (1983) Monkey models of tardive dyskinesia. In: Bannet J, Belmaker RH (eds) New directions in tardive dyskinesia. Karger, Basel, pp 21–33

    Google Scholar 

  • Ellison G, 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

    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 ED, See RE, Gunne LM (1988) Chronic neuroleptics alter the effects on oral movements of the D1 agonist SK&F 38393 and the D2 agonist LY171555. Psychopharmacology 96:253–257

    Google Scholar 

  • Ereshefsky L, Saklad SR, Jann MW, Davis CM, Richards A, Seidel DR (1984) Future of depot neuroleptic therapy: Pharmacokinetic and pharmacodynamic approaches. J Clin Psychiatry 45(5):50–59

    Google Scholar 

  • Fann WE, Stafford J, Malone R, Frost J, Richman B (1977) Clinical research techniques in tardive dyskinesia. Am J Psychiatry 134:759–762

    Google Scholar 

  • Gardos G, Cole JO, Tarsy D (1978) Withdrawal syndromes associated with antipsychotic drugs. Am J Psychiatry 135(11):1321–1324

    Google Scholar 

  • Gardos G, Cole JO, Salomon M, Schnielbolk S (1987) Clinical forms of severe tardive dyskinesia. Am J Psychiatry 144(7):895–902

    Google Scholar 

  • Gimenez-Roldan S, Mateo D, Bartolome P (1985) Tardive dystonia and severe tardive dyskinesia: a comparison of risk factors and prognosis. Acta Psychiatr Scand 71:488–494

    Google Scholar 

  • Goldman MB, Luchins DJ (1984) Intermittent neuroleptic therapy and tardive dyskinesia: a literature review. Hosp Comm Psychiatry 35:1215–1219

    Google Scholar 

  • Gunne LM, Barany S (1976) Haloperidol-induced tardive dyskinesia in monkeys. Psychopharmacology 50:237–240

    Google Scholar 

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

    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 

  • Jeste DV, Wyatt RJW (1982) Therapeutic strategies against tardive dyskinesia: two decades of experience. Arch Gen Psychiatry 39:803–816

    Google Scholar 

  • Kashihara K, Sato M, Fujiwara Y, Harada T, Ogawa T, Otsuki S (1986) Effects of intermittent and continuous haloperidol administration on the dopaminergic system in the rat brain. Biol Psychiatry 21:650–656

    Google Scholar 

  • Koller WC (1984) Effects of intermittent haloperidol treatment on dopamine receptor sensitivity in guinea pigs. Psychopharmacology 84:98–100

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  • Liebman J, Neale R (1980) Neuroleptic-induced acute dyskinesias in squirrel monkeys: correlation with propensity to cause extrapyramidal side effects. Psychopharmacology 68:25–29

    Google Scholar 

  • Marder SR (1986) Depot neuroleptics: side effects and safety. J Clin Psychopharmacology 6(1) Suppl:24S-29S

    Google Scholar 

  • Meldrum BS, Anlezark GM, Marsden CD (1977) Acute dystonia as an idiosyncratic response to neuroleptics in baboons. Brain 100:313–326

    Google Scholar 

  • Midha KK, Cooper JK, Hawes EM, Hubbard JW, Korchinski ED, McKay G (1988) An ultra sensitive method for the measurement of haloperidol and reduced haloperidol in plasma by high-performance liquid chromatography with coulometric detection. Therapeutic Drug Monitoring 10:177–183

    Google Scholar 

  • Murugaiah K, Theodorou A, Clow A, Jenner P, Marsden CD (1985) Effects of discontinuous drug administration on the development of dopamine receptor supersensitivity during chronic trifluoperazine or cis-flupenthixol administration to rats. Psychopharmacology 86:228–232

    Google Scholar 

  • Nair NPV, Suranyi-Cadotte B, Schwartz G, Thavundayil JX, Achim A, Lizondo E, Nayak R (1986) A clinical trial comparing intramuscular haloperidol decanoate and oral haloperidol in chronic schizophrenic patients: efficacy, safety, and dosage equivalence. J Clin Psychopharmacol 6(1) Suppl:30S-37S

    Google Scholar 

  • Neale R, Gerhardt S, Liebman JM (1984) Effects of dopamine agonists, catecholamine depletors, and cholinergic and GABAergic drugs on acute dyskinesias in squirrel monkeys. Psychopharmacology 82:20–26

    Google Scholar 

  • Owen F, Cross AJ, Waddington JL, Poulter M, Gamble SJ, Crow TJ (1980) Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months haloperidol administration. Life Sci 26(1):55–59

    Google Scholar 

  • Post RM (1980) Intermittent versus continuous stimulation: effect of time interval on the development of sensitization or tolerance. Life Sci 26:1275–1282

    Google Scholar 

  • Rondot P, Bathien N (1986) Movement disorders in patients with coexistent neuroleptic-induced tremor and tardive dyskinesia: EMG and pharmacologic study. Adv Neurol 45:361–366

    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, Jenner P, Marsden CD (1985) 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 (1989) The effects of chronic neuroleptic administration on motor behavior and brain receptors in an animal model of tardive dyskinesia. Ph D Dissertation, UCLA, 1989. University Microfilms International Michigan

  • See RE, Sant WW, Ellison GD (1987) Recording oral activity in rats reveals a long-lasting subsensitivity to haloperidol as a function of duration of previous haloperidol treatment. Pharmacol Biochem Behav 28:175–178

    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 

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

    Google Scholar 

  • Waddington JL, Molloy A (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 

  • Weiss B, Santelli S (1978) Dyskinesias evoked in monkeys by weekly administration of haloperidol. Science 200:799–801

    Google Scholar 

  • Wirshing WC, Cummings JL, Lathers P, Engel J (1989) The machine measured characteristics of tardive dyskinesia. Schizophr Res 2(1–2):240

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

See, R.E., Ellison, G. Intermittent and continuous haloperidol regimens produce different types of oral dyskinesias in rats. Psychopharmacology 100, 404–412 (1990). https://doi.org/10.1007/BF02244615

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02244615

Key words

Navigation