Abstract
It is known that a single dose of a neuroleptic can elicit dopaminergic supersensitivity in animals. On the other hand, the clinical syndrome of tardive dyskinesia takes many months or years to develop. To resolve this apparent discrepancy, it is possible that subclinical or latent tardive dyskinesia is fully compensated in most patients taking neuroleptics. In others, where the tardive dyskinesia is full-blown and grossly apparent, the dopaminergic supersensitivity may be decompensated. Such compensatory and decompensatory phases have been proposed earlier by Hornykiewicz (1974), in the case of Parkinson's Disease.
Dopaminergic supersensivity persists for a period proportional to the length of the neuroleptic treatment. It is not yet clear whether the relation between the length of treatment and the persistence of supersensitivity holds for very long treatments but in principle the relationship might account for the persistence of tardive dyskinesia after years of neuroleptic pretreatment.
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References
Ahtee, L., Kaariainen, I.: The effect of narcotic analgesics on the homovanillic acid content of rat nucleus caudatus. Eur. J. Pharmacol. 22, 216–218 (1973)
Ahtee, L.: Catalepsy and stereotypies in the rats treated with methadone: relation to striatal dopamine. Eur. J. Pharmacol. 27, 221–230 (1974)
Anden, N.-E., Butcher, S. G., Corrodi, H., Fuxe, K., Ungerstedt, U.: Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Eur. J. Pharmacol. 11, 303–314 (1970)
Asper, H., Baggiolini, M., Burki, H. R., Lauener, H., Ruch, W., Stille, G.: Tolerance phenomena with neuroleptics. Catalepsy apomorphine stereotypies and striatal dopamine metabolism in the rat after single and repeated administration of loxapine and haloperidol. Eur. J. Pharmacol. 22, 287–294 (1973)
Bowers, M. B., Jr., Rozitis, A.: Regional differences in homovanillic acid concentrations after acute and chronic administration of antipsychotic drugs. J. Pharm. Pharmacol. 26, 743–745 (1974)
Burkard, W. P., Bartholini, G.: Changes in activation of adenylate cyclase and of dopamine turnover in rat striatum during prolonged haloperidol treatment. Experimentia 30, 685 (1974)
Burt, D. R., Creese, I., Snyder, S. H.: Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196, 326–328 (1977)
Burt, D. R., Enna, S. J., Creese, I., Snyder, S. H.: Dopamine receptor binding in the corpus striatum of mammalian brain. Proc. Natl. Acad. Sci. U.S.A. 72, 4655–4659 (1975)
Carlsson, A.: Receptor-mediated control of dopamine metabolism. In: Pre- and postsynaptic receptors. E. Usdin and W. E. Bunney, eds., pp. 49–63. New York: Marcel Dekker 1975
Christensen, A. V., Fjalland, B., Møller Nielsen, I.: On the supersensitivity of dopamine receptors induced by neuroleptics. Psychopharmacology 48, 1–6 (1976)
Clouet, D. H., Iwatsubo, K.: Dopamine-sensitive adenylate cyclase of the caudate nucleus of rats treated with morphine. Life Sci. 17, 35–40 (1975)
Costall, B., Naylor, R. J.: Neuroleptic and non-neuroleptic catalepsy. Arzneim. Forsch. 23, 674–683 (1973)
Costall, B., Naylor, R. J.: The behavioural effects of dopamine applied intracerebrally to areas of mesolimbic system. Eur. J. Pharmacol. 32, 87–92 (1975)
Costentin, J., Marcais, H., Protais, P., Baudry, M., Delabaume, S., Matres, M. P., Schwartz, J. C.: Rapid development of hypersensitivity of striatal dopamine receptors induced by alfamethylparatyrosine and its prevention by protein synthesis inhibitors. Life Sci. 21, 307–314 (1977)
Cox, B., Ary, M., Lomax, P.: Changes in sensitivity to apomorphine during morphine dependence and withdrawal in rats. J. Pharmacol. Exp. Ther. 196, 637–641 (1975)
Crane, G. E.: Persistent dyskinesia. Br. J. Psychiatry 122, 395–405 (1973)
Creese, I., Iversen, S. D.: The role of forebrain dopamine systems in amphetamine induced stereotyped behaviour in the rat. Psychopharmacologia (Berl.) 39, 345–357 (1974)
Dolphin, A., Sawaya, M. C. B., Jenner, P., Marsden, C. D.: Behavioural and biochemical effects of chronic reduction of cerebral noradrenaline receptor stimulation. Naunyn-Schmiedeberg's Arch. Pharmacol. 299, 163–173 (1977)
Dustan, R., Jackson, D. M.: The demonstration of a change in adrenergic receptor sensitivity in the central nervous system of mice after withdrawal from long-term treatment with haloperidol. Psychopharmacology 38, 105–114 (1976)
Dustan, R., Jackson, D. M.: The demonstration of a change in responsiveness of mice to physostigmine and atropine after withdrawal from long-term haloperidol pretreatment. J. Neural Transm. 40, 181–189 (1977)
Engel, J., Liljequist, S.: The effect of long-term ethanol treatment on the sensitivity of the dopamine receptors in the nucleus accumbens. Psychopharmacology 49, 253–257 (1976)
Ezrin-Waters, C., Muller, P., Seeman, P.: Catalepsy induced by morphine or haloperidol effects of apomorphine and anticholinergic drugs. Can. J. Physiol. Pharmacol. 54, 516–519 (1976)
Ezrin-Waters, C., Seeman, P.: Tolerance to haloperidol catalepsy. Eur. J. Pharmacol. 41, 321–327 (1977)
Ezrin-Waters, C., Seeman, P.: Haloperidol-induced tolerance to morphine catalepsy. Life Sci. 21, 419–422 (1977)
Friedhoff, A. J., Bonnet, K., Rosengarten, H.: Reversal of two manifestations of dopamine receptor supersensitivity by administration of L-DOPA. Res. Commun. Chem. Pathol. Pharmacol. 16, 411–423 (1977)
Fukui, K., Takagi, H.: Effect of morphine on cerebral contents of metabolites of dopamine in the normal and tolerant mice: its possible relation to analgesic action. Br. J. Pharmacol. 44, 45–51 (1972)
Fuxe, K.: Tools in the treatment of Parkinson's disease: studies on new types of dopamine receptor stimulating agents. In: Progress in the treatment of Parkinsonism. Advances in neurology, Vol. 3, D. B. Calne, ed., pp. 273–279. New York: Raven 1973
Gessa, G. L., Tagliamonte, A.: Effect of methadone and dextromoramide on dopamine metabolism: comparison with haloperidol and amphetamine. Neuropharmacology 14, 913–920 (1975)
Gianutsos, G., Drawbaugh, R. B., Hynes, M. D., Lal, H.: Behavioural evidence for dopaminergic supersensitivity after chronic haloperidol. Life Sci. 14, 887–898 (1974)
Gianutsos, G., Lal, H.: Alteration in the action of cholinergic and anticholinergic drugs after chronic haloperidol: indirect evidence for cholinergic hyposensitivity. Life Sci. 18, 515–520 (1976)
Gianutsos, G., Thornburg, J. E., Moore, K. E.: Differential actions of dopamine agonists and antagonists on γ-butyrolactone-induced increase in mouse brain dopamine. Psychopharmacology 50, 225–229 (1976)
Gianutsos, G., Moore, K. E.: Dopaminergic supersensitivity in striatum and olfactory tubercle following chronic administration of haloperidol or clozapine. Life Sci. 20, 1585–1592 (1977)
Gnegy, M., Uzunov, P., Costa, E.: Participation of an endogenous Ca++-binding protein activator in the development of drug-induced supersensitivity of striatal dopamine receptors. J. Pharmacol. Exp. Ther. 202, 558–564 (1977)
Griffiths, P. J., Littleton, J. M., Ortiz, A.: Changes in monoamine concentrations in mouse brain associated with ethanol dependence and withdrawal. Br. J. Pharmacol. 50, 489–494 (1974)
György, L., Pfeifer, K. A., Hajtman, B.: Modification of certain central nervous effects of haloperidol during long-term treatment in the mouse and rat. Psychopharmacologia (Berl.) 16, 223–233 (1969)
Heal, D. J., Green, A. R., Boullin, D. J., Graham-Smith, D. G.: Single and repeated administration of neuroleptic drugs to rats: effect on striatal dopamine-sensitive adenylate cyclase and locomotor activity produced by tranylcypromine and l-tryptophan or l-dopa. Psychopharmacology 49, 287–300 (1976)
Hicks, J., Strong, R., Smith, R. C., Samorajski, T.: Behavioural supersensitivity to bromocriptine in mice. Society for Neuroscience abstract, III, p. 441, No. 1406 (1977)
Hoffman, P. L., Tabakoff, B.: Alterations in dopamine receptor sensitivity by chronic ethanol treatment. Nature 268, 551–552 (1977)
Hornykiewicz, O.: The mechanisms of action of L-DOPA in Parkinson's disease. Life Sci. 15, 1249–1259 (1974)
Iwatsubo, K., Clouet, D. H.: Dopamine-sensitive adenylate cyclase of the caudate nucleus of rats treated with morphine or haloperidol. Biochem. Pharmacol. 24, 1499–1503 (1975)
Jackson, D. M., Andén, N.-E., Engel, J., Liljequist, S.: The effect of long-term penfluridol treatment on the sensitivity of the dopamine receptors in the nucleus accumbens and the corpus striatum. Psychopharmacologia (Berl.) 45, 151–155 (1975)
Jackson, D. M., Andén, N.-E., Dahlström, A.: A functional effect of dopamine in the nucleus accumbens and in some other dopamine-rich parts of the rat brain. Psychopharmacologia (Berl.) 45, 139–149 (1975)
Keller, H. H., Bartholini, G., Pletscher, A.: Increase of 3-methoxy-4-hydroxyphenylethylene glycol in rat brain by neuroleptic drugs. Eur. J. Pharmacol. 23, 183–186 (1973)
Klawans, H. L., Crossett, P., Dana, N.: Effect of chronic amphetamine exposure on stereotyped behaviour: implications for pathogenesis of L-Dopa-induced dyskinesias. In: Dopaminergic mechanisms. Advances in neurology, Vol. 9, D. Calne, T. N. Chase and A. Barbeau, eds., pp. 105–112, New York: Raven 1975
Klawans, H. L., Margolin, D. I.: Amphetamine-induced dopaminergic hypersensitivity in guinea-pigs. Arch. Gen. Psychiatry 32, 725–732 (1975)
Klawans, H. L., Goetz, C., Nausieda, P. A., Weiner, W. J.: Levodopa-induced dopamine receptor hypersensitivity. Ann. Neurology 2, 125–129 (1977)
Kobayashi, R. M., Fields, J. Z., Hruska, R. E., Beaumont, K., Yamamura, H. I.: Brain neurotransmitter receptors and chronic antipsychotic drug treatment: a model for tardive dyskinesia. In: Animal models in psychiatry. E. Usdin, ed. pp. 405–409. New York: Pergamon 1978
Kuschinsky, K., Hornykiewicz, O.: Morphine catalepsy in rat: relation to striatal dopamine metabolism. Eur. J. Pharmacol. 19, 119–122 (1972)
Kuschinsky, K.: Dopamine receptor sensitivity after repeated morphine administrations to rats. Life Sci. 17, 43–48 (1975)
Lerner, P., Nosé, P.: Haloperidol: effect of long-term treatment on rat striatal dopamine synthesis and turnover. Science 197, 181–183 (1977)
Leysen, J., Tollenaere, J. P., Koch, M. H. J., Laduron, P.: Differentiation of opiate and neuroleptic receptor binding in rat brain. Eur. J. Pharmacol. 43, 253–267 (1977)
Marsden, C. D., Tarsy, D., Baldessarini, R. J.: Spontaneous and drug-induced movement disorders in psychotic patients. In: Psychiatric aspects of neurologic disease. D. F. Benson and D. Blumer, eds., pp. 219–265. New York: Grune & Stratton 1975
Martres, M. P., Costentin, J., Baudry, M., Marcais, H., Protais, P., Schwartz, J. C.: Long-term changes in the sensitivity of pre- and postsynaptic dopamine receptors in mouse striatum evidenced by behavioural and biochemical studies. Brain Res. 136, 319–337 (1977)
Merali, Z., Singhal, R. L., Hrdina, P. D., Ling, G. M.: Changes in brain cyclic AMP metabolism and acetylcholine and dopamine during narcotic dependence and withdrawal. Life Sci. 16, 1889–1894 (1975)
Møller Nielsen, I., Fjalland, B., Pedersen, V., Nymark, M.: Pharmacology of neuroleptics upon repeated administration. Psychopharmacologia (Berl.) 34, 95–104 (1974)
Muller, P., Seeman, P.: Increased specific neuroleptic binding after chronic haloperidol in rats. Soc. Neurosci. Abstr. 2, 874 (1976)
Muller, P., Seeman, P.: Brain neurotransmitter receptors after long-term haloperidol: dopamine, acetylcholine, serotonin, α-noradrenergic and naloxone receptors. Life Sci. 21, 1751–1758 (1977)
Pijnenburg, A. J. J., Honing, W. M. M., Van Der Heyden, J. A. M., Van Rossum, J. M.: Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity. Eur. J. Pharmacol. 35, 45–58 (1976)
Puri, S. K., Lal, H.: Tolerance to the behavioural and neurochemical effects of haloperidol and morphine in rats chronically treated with morphine or haloperidol. Naunyn-Schmiedeberg's Arch. Pharmacol. 282, 155–170 (1974)
Puri, S. K., Volicer, L., Cochin, J.: Changes in the striatal adenylate cyclase activity following acute and chronic morphine treatment and during withdrawal. J. Neurochem. 27, 1551–1554 (1976)
Quitkin, F., Rifkin, A., Gochfeld, L., Klein, D. F.: Tardive dyskinesia: are first signs reversible? Am. J. Psychiatry 134, 84–87 (1977)
Riffee, W. H., Gerald, M. C.: The effect of chronic administration and withdrawal of (+)-amphetamine on seizure threshold and endogenous catecholamine concentrations and their rates of biosynthesis in mice. Psychopharmacology 51, 175–179 (1977)
Rotrosen, J., Friedman, E., Gershon, S.: Striatal adenylate cyclase activity following reserpine and chronic chlorpromazine administration in rats. Life Sci. 17, 563–568 (1975)
Sasame, H. A., Perez-Cruet, J.: Evidence that methadone blocks dopamine receptors in the brain. J. Neurochem. 19, 1953–1957 (1972)
Sayers, A. C., Bürki, H. R., Ruch, W. Asper, H.: Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia (Berl.) 41, 97–104 (1975)
Scatton, B., Glowinski, J., Julou, L.: Dopamine metabolism in the mesolimbic and mesocortical dopaminergic systems after single or repeated administrations of the neuroleptics. Brain Res. 109, 184–189 (1976)
Seeber, U., Kuschinsky, K.: Dopamine-sensitive adenylate cyclase in homogenates of rat striata during ethanol and barbiturate withdrawal. Arch. Toxicol. (Berl.) 35, 247–253 (1976)
Seeman, P., Chau-Wong, M., Tedesco, J., Wong, K.: Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc. Natl. Acad. Sci. U.S.A. 72, 4376–4380 (1975)
Smith, R. C., Davis, J. M.: Behavioural evidence for supersensitivity after chronic administration of haloperidol, clozapine and thioridazine. Life Sci. 19, 725–732 (1976)
Tang, L. C., Cotzias, G. C.: L-3,4-Dihydroxyphenylalanine-induced hypersensitivity simulating features of denervation. Proc. Natl. Acad. Sci. U.S.A. 74, 2126–2129 (1977)
Tarsy, D., Baldessarini, R. J.: Behavioural supersensitivity to apomorphine following chronic treatment with drugs which interfere with synaptic function of catecholamines. Neuropharmacology 13, 927–940 (1974)
Tarsy, D., Baldessarini, R. J.: The pathophysiologic basis of tardive dyskinesia. Biol. Psychiatry 12, 431–450 (1977)
U'Prichard, D. C., Greenberg, D. A., Snyder, S. H.: Binding characteristics of radiolabeled agonist and antagonist at central nervous system alpha noradrenergic receptors. Mol. Pharmacol. 13, 454–473 (1977)
Von Stralendorff, V. B., Ackenheil, M., zimmermann, J.: Akute und chronische Wirkung von Carpipramin, Clozapin, Haloperidol und Sulpirid auf den Stoffwechsel biogener Amine im Rattengehirn. Arzneim. Forsch. 26, 1096–1098 (1976)
Von Voigtlander, P. F., Losey, E. G., Triezenberg, H. J.: Increased sensitivity to dopaminergic agents after chronic neuroleptic treatment. J. Pharmacol. Exp. Ther. 193, 88–94 (1975)
Walters, J. R., Roth, R. H.: Dopamine neurons: an in vivo system for measuring drug interactions with presynaptic receptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 296, 5–14 (1976)
Worms, P., Scatton, B.: Tolerance to stereotyped behaviour and to decrease in striatal homovanillic acid levels after repeated treatment with apomorphine dipivaloyl ester. Eur. J. Pharmacol. 45, 395–396 (1977)
Yarborough, G.: Supersensitivity of caudate neurones after repeated administration of haloperidol. Eur. J. Pharmacol. 31, 367–369 (1975)
Zarcone, V., Barchas, J., Hoddes, E., Montplaisir, J., Sack, R., Wilson, R.: Experimental ethanol ingestion: sleep variables and metabolites of dopamine and serotonin in the cerebrospinal fluid. In: Alcohol intoxication and withdrawal. Vol. 2, M. M. Gross, ed., pp. 431–451. New York: Plenum 1975
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Muller, P., Seeman, P. Dopaminergic supersensitivity after neuroleptics: Time-course and specificity. Psychopharmacology 60, 1–11 (1978). https://doi.org/10.1007/BF00429171
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DOI: https://doi.org/10.1007/BF00429171