Abstract
Persistent tardive dyskinesia is a serious side effect of long-term treatment with neuroleptics. Although striatal pathologic changes are believed to underlie this potentially irreversible iatrogenic syndrome, the nature of the neuroleptic-induced neuropathology is unclear. In the present study, we treated rats with either vehicle or fluphenazine decanoate (5 mg/kg, IM) every 2 weeks for 4, 8 or 12 months. Four to nine weeks after the last injection, the animals were sacrificed and the density of cells in the central part of the striatum was measured with a computerized image-analysis system. The control and experimental animals did not differ in body weight with 4 and 8 months of treatment, but the rats treated with fluphenazine for 12 months had significantly lower body weights than comparable controls. Four months of neuroleptic use produced no significant neuropathologic changes. The animals treated with fluphenazine for 8 months had a significantly lower density of the large neurons. In the 12-month-treated group, there was no significant difference between the control and experimental animals, probably because of a ‘floor effect’: the density of the large neurons was significantly lower in the 12-month-treated compared to the 8-month-treated control rats.
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References
Benes FM, Paskevich PA, Domesick V (1983) Haloperidol-induced plasticity of axon terminals in rat substantia nigra. Science 221: 969–971
Benes FM, Paskevich PA, Davidson J, Domesick VB (1985) The effects of haloperidol on synaptic patterns in the rat striatum. Brain Res 329: 265–274
Brizzee KR, Samorajski T, Smith RC, Brizzee DL (1981) The effect of age and chronic neuroleptic drug treatment on cell populations in the neostriatum of Fischer 344 rats. In: Enna SJ, Samorajski T, Beer B (eds) Brain neurotransmitters and receptors in aging and age related disorders. Raven Press, New York, pp 59–80
Cadet JL, Lohr JB, Jeste DV (1987) Tardive dyskinesia and schizophrenic burnout: the possible involvement of cytotoxic free radicals. In: Henns FA, DeLisi LE (eds) Handbook of schizophrenia, vol. 2: The neurochemistry and pharmacology of schizophrenia, Elsevier, amsterdam, Chapter 15
Casey DE (1987) Tardive dyskinesia. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, pp 1411–1419
Cazullo CL, Goldwurm GF, Vanni F (1965) Correlations between chemical structures of psychotropic drugs and histological features experimentally induced in the central nervous system. In: Luthy F, Bischoff A (eds) Proceedings of the Fifth International Congress of Neuropathology. Excerpta Medica, Amsterdam, pp 842–853
Chang HT (1988) Dopamine-acetylcholine interaction in the rat striatum: a dual-labeling immunocytochemical study. Brain Res Bull 21: 295–304
Clow A, Jenner P, Marsden CD (1979) Changes in dopaminemediated behavior during one year’s neuroleptic administration. Eur J Pharm 57: 365–375
Clow A, Theodorou A, Jenner P, Marsden CD (1980) Changes in rat striatal dopamine turnover and receptor activity during one year’s neuroleptic administration. Eur J Pharmacol 63: 135–144
Dom R (1967) Local glial reaction in the CNS of albino-rats in response to the administration of a neuroleptic drug (butyrophenone). Acta Neurol Psychiatr Belg 67: 755–762
Ebadi M, Hama Y (1988) Dopamine, GABA, cholecystokinin and opioids in neuroleptic-induced tardive dyskinesia. Neurosci Biobehav Rev 12: 179–187
Gerlach J (1975) Long-term effect of perphenazine on the substantia nigra in rats. Psychopharmacologia 45: 51–54
Gross H, Kaltenbach E (1969) Neuropathological findings in persistent hyperkinesia after neuroleptic long-term therapy. In: Cerletti A, Bove FJ (eds) The present status of psychotropic drugs. Excerpta Medica, Amsterdam
Groves PM (1983) A theory of the functional organization of the neostriatum and the neostriatal control of voluntary movement. Brain Res 286: 109–132
Hackenberg P, Lange E (1975) Tierexperimenteller Beitrag zum problem der irreversiblen hirnschadigung bei der neurolepticalangzeittherapie. Exp Pathol 10: 132–142
Jellinger K (1977) Neuropathologic findings after neuroleptic longterm therapy. In: Roizin L, Shniraki H, Greevic N (eds) Neurotoxicology. Raven Press, New York
Jeste DV, Wyatt RJ (1982) Understanding and treating tardive dyskinesia. Gilford Press, New York
Kane JM, Woerner M, Lieberman J (1988) Tardive dyskinesia: prevalence, incidence and risk factors. J Clin Psychopharmacol 8 [4 (suppl)]: 52S-56S
Kemp JM, Powell TPS (1971) The synaptic organization of the caudate nucleus. Phil Trans R Soc Lond B. 262: 403–412
Kimura H, McGeer PL, Peng I, McGeer EG (1980) Choline acetyltransferase-containing neurons in rodent brain demonstrated by immunohistochemistry. Science 208: 1057–1059
Konigsmark BW, Kalyanaraman UP, Corey P, Murphy EA (1969) An evaluation of techniques in neuronal population estimates: The sixth nerve nucleus. J Hopkins Med J, 125: 146
Kubota Y, Inagaki S, Shimada S, Kito S, Eckenstein F, Tohyama M. Neostriatal cholinergic neurons receive direct synaptic inputs from dopaminergic axons. Brain Res 413: 179–184
Lam RW, Jeste SD, Jeste DV (1988) Preventing neuroleptic-induced tardive dyskinesia in adults and children. L’Encephale 14: 251–255
Lane RF, Blaha CD (1987) Chronic haloperidol decreases dopamine release in striatum and nucleus accumbens in vivo: depolarization block as a possible mechanism of action. Brain Res Bull 18: 135–138
Lohr JB, Wisniewski A, Jeste DV (1986) Neurological aspects of tardive dyskinesia. In: Nasrallah HA, Weinberger DR (eds) The Neurology of schizophrenia. Elsevier, Amsterdam, pp 97–119
Lohr JB, Cadet JL, Lohr MA, Larson L, Wasli E, Wade L, Hylton R, Vidoni C, Jeste DV, Wyatt RJ (1988) Vitamin E in the treatment of tardive dyskinesia: The possible involvement of free radical mechanisms. Schizophren Bull 14: 291–296
Mackiewicz J, Gershon S (1964) An experimental study of the neuropathological and toxicological effects of chlorpromazine and reserpine. J Neuropsychiatry 5: 159–169
Mahadik SP, Laev H, Korenovsk A, Karpiak SE (1988) Haloperidol alters rat CN8 colinergic system: enzymatic and morphological analyses. Biol Psychiatry 24: 199–217
Meshul CK, Casey DE (1989) Regional, reversible ultrastructural changes in rat brain with chronic neuroleptic treatment. Brain Res 489[2]: 338–346
Nielsen EB, Lyon M (1978) Evidence for cell loss in corpus striatum after long-term treatment with a neuroleptic drug (fluphenthixol) in rats. Psychopharmacology, 59: 85–89
Pakkenberg H, Fog R (1974) Short-term effect of perphenazine enanthate on the rat brain. Psychopharmacologia 40: 165–169
Pakkenberg H, Fog R Nilakantan B (1973) The long-term effect of perphenazine enanthate on the rat brain. Some metabolic and anatomical observations. Psychopharmacologia 29: 329–336
Pandurangi AK, Devi V, Channabasavanna SM (1980) Caudate atrophy in tardive dyskinesia (a pneumoencephalographic study). J Clin Psychiatry 41: 229–231
Pasik P, Pasik T, DiFiglia M (1979) The internal organization of the neostriatum in mammals. In: Divac I, Obers RGE (eds) The neostriatum. Pergamon Press, New York, pp 5–36
Paxinos E, Watson C (1986) Rat brain in stereotoxic coordinates, 2nd edn. Academic Press, Orlando, Florida, p 36
Pedata F, Sorbi S, Pepeu G (1980) Choline high-affinity uptake and metabolism and choline acetyltransferase activity in the striatum of rats chronically treated with neuroleptics. J Neurochem 35: 606–611
Roizin L, True C, Knight M (1959) Structural effects of tranquilizers. Res Publ Assoc Res Nerv Ment Dis 37: 285–324
Rupniak NMJ, Jenner P, Marsden CD (1983) The effect of chronic neuroleptic administration on cerebral dopamine receptor function. Life Sci 32: 2289–2311
Rupniak NMJ, Briggs RS, Petersen MM, Mann S, Reavill C, Jenner P, Marsden CD (1986) Differential alterations in striatal acetylcholine function in rats during 12 months continuous administration of haloperidol, sulpiride, or clozapine. Clin Neuropharmacol 9: 282–292
Sethy VH, Van Woert MH (1974a) Brain acetylcholine and cholinesterase; effects of phenothiazines and physostigmal interactions in rats. J Neurochem 23: 105–109
Sethy VH, Van Woert MH (1974b) Regulation of striatal AcH concentration by dopamine receptors. Nature 251: 529–530
Sommer H, Quandt J (1970) Langzeitbehandlung mit Chlor-promazin im Tierexperiment. In: Proceedings of the Sixth International Congress of Neuropathology. Masson & Cie, Paris, pp 466–491
Tarsy D, Baldessarini RJ (1974) Behavioural supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines. Neuropharmacology 13: 927–940
Terry RD, Peck A, DeTeresa R, Schechter R, Horoupian DS (1981) Some morphometric aspects of the brain in senile dementia of the Alzheimer type. Ann Neurol 10: 184–192
Terry RD, DeTeresa R (1982) The importance of video editing in automated image analysis in studies of the cerebral cortex. J Neurol Sci 53:413–421
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Parts of this work was presented at the annual meetings of the Society for Neuroscience in Phoenix, Arizona on November 2. 1989, and the American College of Neuropsychopharmacology in Maui. Hawaii on December 15, 1989
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Jeste, D.V., Lohr, J.B. & Manley, M. Study of neuropathologic changes in the striatum following 4, 8 and 12 months of treatment with fluphenazine in rats. Psychopharmacology 106, 154–160 (1992). https://doi.org/10.1007/BF02801966
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DOI: https://doi.org/10.1007/BF02801966