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The effects of dose and duration of chronic pimozide adminstration on dopamine receptor supersensitivity

  • Kevin J. Dewey
  • H. C. Fibiger
Article

Summary

The neuroleptic drug pimozide was administered chronically to rats at different doses (0.75, 1.5 or 3.0 mg/kg, twice daily for 10 days) or for different durations (1.5 mg/kg twice daily for 5, 10, 20 or 40 days). At various intervals (4–40 days) after withdrawal dopamine (DA) receptor density in the striatum was assessed directly using specific [3H]-spiroperidol binding and indirectly by means of apomorphine-induced stereotypy and amphetamine-induced locomotor activity. The incease in the density of DA receptors was shown to be dependent upon the dose but not upon the duration of chronic pimozide. In contrast, the enhanced apomorphine-induced stereotypy was influenced by the duration but not by the dose of chronic pimozide. The potentiation of d-amphetamine-induced locomotor activity was found to vary as a function of both dose and duration of chronic pimozide administration. The results indicate that the augmentation of these apomorphine- and amphetamine-induced behaviors cannot be attributed solely to striatal DA receptor supersensitivity and that other, presently unspecified factors must contribute. It is also argued that in the absence of pharmacologically-induced DA receptor stimulation, the functional consequences of neuroleptic-induced increases in the density of striatal DA receptors are not apparent and remain unknown. In addition, these findings support the view that neuroleptic-induced proliferation of DA receptors cannot be the sole mechanism underlying tardive dyskinesia in man.

Key words

Supersensitivity Chronic neuroleptics Dopamine receptors Apomorphine Amphetamine 

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References

  1. Burt DR, Enna SJ, Creese I, Snyder SH (1975) Dopamine receptor binding in the corpus striatum of mammalian brain. Proc Natl Acad Sci USA 72:4655–4659Google Scholar
  2. Burt DR, Creese, I, Snyder SH (1976) Properties of [3H]-haloperidol and [3H]-dopamine binding associated with dopamine receptors in calf brain membranes. Mol Pharmacol 12:800–812Google Scholar
  3. Burt DR, Creese I, Snyder S (1977) Anti-schizophrenic drugs — chronic treatment elevates DA receptor binding in the brain. Science 196:326–328Google Scholar
  4. Carlsson A, Lindqvist (1963) Effect of chlorpromazine and haloperidol on formation of 3-methoxytryptamine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20:140–144Google Scholar
  5. Christensen AV, Fjalland B, Moller-Nielsen I (1976) On the supersensitivity of dopamine receptors induced by neuroleptics. Psychopharmacology 48:1–6Google Scholar
  6. Clow A, Jenner P, Marsden CD (1979) Changes in dopamine-mediated behavior during one year's neuroleptic administration. Eur J Pharmacol 57:365–375Google Scholar
  7. Clow A, Theodoru A, Jenner P, Marsden CD (1980) Cerebral dopamine function in rats following withdrawal from one year of continuous neuroleptic administration. Eur J Pharmacol 63:145–157Google Scholar
  8. Crane GE (1971) Persistence of neurological symptoms due to neuroleptic drugs. Am J Psychiatry 127:1407–1410Google Scholar
  9. Creese I, Iversen SD (1975) The pharmacological and anatomical substrates of the amphetamine response in the rat. Brain Res 83:419–436Google Scholar
  10. Creese I, Snyder SH (1977) A simple and sensitive radioreceptor assay for antischizophrenic drugs in blood. Nature 270:180–182Google Scholar
  11. Degkwitz R, Binsack KF, Herbert H, Luxenburger O, Wenzel W (1967) Zum Probleme der persistierenden Hyperkinesen nach langfristiger Anwendung von Neuroleptika. Nervenarzt 38:170–174Google Scholar
  12. Dunstan R, Jackson DM (1977) The effects of apomorphine and clonidine on locomotor activity in mice after long term treatment with haloperidol. Clin Exp Pharmacol Physiol 4:131–141Google Scholar
  13. Ernst AM (1967) Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats. Psychopharmacology 10:316–324Google Scholar
  14. Fuxe K, Ungerstedt U (1976) Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Eur J Pharmacol 11:303–314Google Scholar
  15. Gerlach J, Reisby N, Randrup A (1974) Dopaminergic hypersensitivity and cholinergic hypofunction in the pathophysiology of tardive dyskinesia. Psychopharmacology 34:21–35Google Scholar
  16. Gianutsos G, Drawbaugh RB, Hynes MD, Lal H (1974) Behavioral evidence for dopaminergic supersensitivity after chronic haloperidol. Life Sci 14:887–894Google Scholar
  17. Gunne LM, Barany S (1976) Haloperidol-induced tardive dyskinesia in monkeys. Psychopharmacology 50:237–240Google Scholar
  18. Holmes JC, Rutledge CO (1976) Effects of the d- and h-isomers of amphetamine on uptake release and catabolism of norepinephrine dopamine and 5-hydroxytryptamine in several regions of rat brain. Biochem Pharmacol 25:447–451Google Scholar
  19. Hunter R, Earl CJ, Thornicroft S (1964) An apparently irreversible syndrome of abnormal movements following phenothiazine medication. Proc R Soc Med 57:758–762Google Scholar
  20. Hyttel J (1979) Neurochemical parameters in the hyperresponsive phase after a single dose of neuroleptics to mice. J Neurochem 33:641–646Google Scholar
  21. Jackson DM, Anden NE, Engel J, Liljequist S (1975) The effect of long term penfluridol treatment on the sensitivity of dopamine receptors in the nucleus accumbens and in the corpus striatum. Psychopharmacology 45:151–155Google Scholar
  22. Jacobsen G, Baldessarini RJ, Manschreck T (1974) Tardive and with-drawal dyskinesia associated with haloperidol. Am J Psychiatry 131:910–913Google Scholar
  23. Kamer RS, Turi AR, Solomon PR, Kaplan LJ (1981) Increased mesolimbic dopamine binding following chronic haloperidol treatment. Psychopharmacology 72:261–263Google Scholar
  24. Kazamatsuri H, Chien C, Cole JO (1972) Treatment of tardive dyskinesia. Arch Gen Psych 27:95–103Google Scholar
  25. Klawans HL, Rubovits H (1972) An experimental model of tardive dyskinesia. J Neural Trans 33:235–246Google Scholar
  26. Klawans HL (1973) The pharmacology of tardive dyskinesia. Am J Psychiatry 130:82–86Google Scholar
  27. Kobayashi RM, Fields JZ, Hruska RE, Beaumont K, Yamamura HI (1978) Brain neurotransmitter receptors and chronic antipsychotic drug treatment: A model for tardive dyskinesia. In: Hanin I, Usdin E (eds) Animal models in psychiatry and neurology. Pergamon Press Ltd, New York, pp 405–410Google Scholar
  28. Koslowski MR, Sawyer S, Marshall JF (1980) Behavioral effects and supersensitivity following nigral dopamine receptor stimulation. Nature 287:52–54Google Scholar
  29. Martres MP, Costentin J, Bandry M, Marcais H, Protais P, Schwartz JC (1977) Long-term changes in the sensitivity of pre-and postsynaptic dopamine receptors in mouse striatum evidenced by behavioral and biochemical studies. Brain Res 136:319–337Google Scholar
  30. McKinney WT, Moran EC, Kraemer GW, Prange Jr AJ (1980) Longterm chlorpromazine in rhesus monkeys: Production of dyskinesias and changes in social behavior. Psychophamacology 72:35–39Google Scholar
  31. Moller-Nielsen I, Fjallano B, Pedersen V, Nymack M (1974) Pharmacology of neuroleptics upon repeated administration. Psychopharmacology 34:95–104Google Scholar
  32. Muller P, Seeman P (1977) Brain neurotransmitter receptors after long term haloperidol: Dopamine acetylcholine, serotonin α-noradrenergic and naloxone receptors. Life Sci 21:1751–1758Google Scholar
  33. Muller P, Seeman P (1978) Dopaminergic supersensitivity after neuroleptics: Time course and specificity. Psychophamacology 60:1–11Google Scholar
  34. Price MTC, Fibiger HC (1974) Apomorphine and amphetamine stereotypy after 6-hydroxydopamine lesions of the substantia nigra. Eur J Pharmacol 29:249–252Google Scholar
  35. Rastogi RB, Singhal RL, Lapierre YD (1981) Effects of short- and long-term neuroleptic treatment on brain serotonin synthesis and turnover: Focus on the serotonin hypothesis of schizophrenia. Life Sci 29:735–741Google Scholar
  36. Rosenthal HE (1967) A graphic method for the determination and presentation of binding parameters in a complex system. Anal Biochem 20:525–532Google Scholar
  37. Roth RH (1979) Dopamine autoreceptors: Pharmacology, function and comparison with post-synaptic dopamine receptors. Comm Psychopharmacol 3:429–445Google Scholar
  38. Sahakian BJ, Robbins TL, Iversen SD (1976) α-Flupenthixol-induced hyperactivity by chronic dosing in rats. Eur J Pharmacol 37:169Google Scholar
  39. Sayers AC, Burki HR, Ruch W, Asper H (1975) Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesia. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacology 41:97–104Google Scholar
  40. Scatchard G (1949) The attraction of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672Google Scholar
  41. Schelkunov EL (1967) Adrenergic effect of chronic administration of neuroleptics. Nature 214:1210–1213Google Scholar
  42. Schmidt WR, Jarcho LW (1966) Persistent dyskinesia following phenothiazine therapy. Arch Neurol 14:369–377Google Scholar
  43. Sedvall G, Fyro B, Nyback H, Wiesel FA (1975) Actions of dopaminergic antagonists in the striatum. In: Calne DB, Chase TN, Barbeau A (eds) Advances in neurology, vol 9. Raven Press, New York, pp 131–140Google Scholar
  44. Smith RC, Davis JM (1976) Behavioral evidence for supersensitivity after chronic administration of haloperidol, clozapine and thioridazine. Life Sci 19:725–732Google Scholar
  45. Staunton DA, Wolfe BB, Groves PM, Molinoff PB (1981) Dopamine receptor changes following destruction of the nigrostriatal pathway: Lack of a relationship to rotational behavior. Brain Res 211: 315–327Google Scholar
  46. Tarsy D, Baldessarini RJ (1974) Behavioral supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines. Neuropharmacology 13:927–940Google Scholar
  47. Thornburg JE, Moore KE (1974) Supersensitivity to dopaminergic agonists following withdrawal of a chronic diet containing haloperidol or pimozide. Pharmacologist 16:307Google Scholar
  48. Voith K (1977) Comparison of behavioral supersensitivity to apomorphine after fluphenazine dihydrochloride and fluphenazine decandate treatment in rats. Prog Neuro Psychopharmacol 1:289–295Google Scholar
  49. Weiss B, Santelli S, Lusink K (1977) Movement disorders induced in monkeys by chronic haloperidol treatment. Psychopharmacology 53:289Google Scholar
  50. Yarbrough GG (1975) Supersensitivity of caudate neurones after repeated administration of haloperidol. Eur J Pharmacol 31: 367–369Google Scholar

Copyright information

© Springer-Verlag 1983

Authors and Affiliations

  • Kevin J. Dewey
    • 1
  • H. C. Fibiger
    • 1
  1. 1.Division of Neurological Sciences Department of PsychiatryUniversity of British ColumbiaVancouverCanada

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