A study on the action of two calcium channel blockers (verapamil and flunarizine) upon an experimental model of tardive dyskinesia in rats

Pereira, João S.; Bertolucci, Paulo H. P.; Ferraz, Henrique B.; Andrade, Luiz A. F. de

doi:10.1590/S0004-282X1992000300001

Abstracts

Tardive dyskinesia (TD), a serious complications of neuroleptic chronic use, has no effective therapy yet. We performed an experiment to study the action on TD, of the calcium channel blockers (CCB) drugs, verapamil and flunarizine. We obtained the TD model in rats, administering haloperidol for a 21-day period. After this, the stereotyped movement induced by apomorphyne was rated. The CCB drugs were administered in acute (in the 28th. day) and chronic (for 8 days, after the 25th day) experiments. Acutely, verapamil increased the stereotyped behaviour, and promoted a reduction of it in the chronic experiment. The results suggest that CCB drugs should be tested in clinical trials of TD.

tardive dyskinesia; calcium channel blockers drugs; neuroleptics

A discinesia tardia (DT) é complicação decorrente do uso prolongado de neuro-lépticos. Até o presente, nenhum tratamento provou ser eficaz na DT. Evidências indiretas apontam para a ação de drogas bloqueadoras de canais de cálcio (BCC) em algumas vias neurais. A ação de duas dessas drogas, verapamil e flunarizina, foi testada em modelo experimental de DT em rato, neste estudo. O haloperidol foi administrado por 21 dias e indução de movimentos estereotipados era obtida no 24º dia, com a injeção de apomorfina. As drogas BCC foram administradas por uma vez no 28º dia (experimento agudo) e por 8 dias, após o 25º dia (experimento crônico). A flunarizina não induziu modificação no padrão de estereotipia dos animais, mas o verapamil levou a aumento no experimento agudo e a diminuição no experimento crônico. Estes achados indicam que as drogas BCC podem ter alguma ação sobre a DT e que ensaios clínicos devem ser feitos para se comprovar se tal ação ocorre no homem.

discinesia tardia; drogas bloqueadoras de canais de cálcio; neuro-lépticos

João S. Pereira^I; Paulo H. P. Bertolucci^II; Henrique B. Ferraz^I; Luiz A. F. de Andrade^III

^IPostgraduate in Neurology. Sector for Investigation of Extrapyradimal Diseases, Department of Neurology and Neurosurgery, Escola Paulista de Medicina

^IIAssociate Professor of Neurology. Sector for Investigation of Extrapyradimal Diseases, Department of Neurology and Neurosurgery, Escola Paulista de Medicina

^IIIAssociate Professor of Neurology and Head of the Sector. Sector for Investigation of Extrapyradimal Diseases, Department of Neurology and Neurosurgery, Escola Paulista de Medicina

SUMMARY

Tardive dyskinesia (TD), a serious complications of neuroleptic chronic use, has no effective therapy yet. We performed an experiment to study the action on TD, of the calcium channel blockers (CCB) drugs, verapamil and flunarizine. We obtained the TD model in rats, administering haloperidol for a 21-day period. After this, the stereotyped movement induced by apomorphyne was rated. The CCB drugs were administered in acute (in the 28th. day) and chronic (for 8 days, after the 25th day) experiments. Acutely, verapamil increased the stereotyped behaviour, and promoted a reduction of it in the chronic experiment. The results suggest that CCB drugs should be tested in clinical trials of TD.

Keywords: tardive dyskinesia, calcium channel blockers drugs, neuroleptics.

RESUMO

A discinesia tardia (DT) é complicação decorrente do uso prolongado de neuro-lépticos. Até o presente, nenhum tratamento provou ser eficaz na DT. Evidências indiretas apontam para a ação de drogas bloqueadoras de canais de cálcio (BCC) em algumas vias neurais. A ação de duas dessas drogas, verapamil e flunarizina, foi testada em modelo experimental de DT em rato, neste estudo. O haloperidol foi administrado por 21 dias e indução de movimentos estereotipados era obtida no 24º dia, com a injeção de apomorfina. As drogas BCC foram administradas por uma vez no 28º dia (experimento agudo) e por 8 dias, após o 25º dia (experimento crônico). A flunarizina não induziu modificação no padrão de estereotipia dos animais, mas o verapamil levou a aumento no experimento agudo e a diminuição no experimento crônico. Estes achados indicam que as drogas BCC podem ter alguma ação sobre a DT e que ensaios clínicos devem ser feitos para se comprovar se tal ação ocorre no homem.

Palavras-chave: discinesia tardia, drogas bloqueadoras de canais de cálcio, neuro-lépticos.

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

Acknowledgments We are grateful to the Department of Psychobiology of Escola Paulista de Medicina for allowing us to use their facilities (animals, laboratories and technical personal).

Dr. Henrique Ballalai Ferraz Disciplina de Neurologia, (Setor de Investigação em Doenças Extrapiramidais), Escola Paulista de Medicina - Rua Botucatu 740 - 04023 São Paulo SP - Brasli.

1. Andrade LAF, Bertolucci PHF, Pereira JS. Discinesia tardia: fisiopatologia e tratamento. Arq. Neuro-Psiquiat (São Paulo) 1984, 42:362-370.
2. Barrow N, Childs A. An anti-tardive-dyskinesia effect of verapamil. Am J Psychiatry 1986, 143:1485.
3. Borison RL, Hitri A, Blowers AJ, Diamond BI. Antipsychotic drug action: clinical, biochemical, and pharmacological evidence for site specificity of action. Clin Neuropharmacol 1983, 6:137-150.
4. Bruin VMS. Estudo da ação de um bloqueador de canais de cálcio (nifedipina) em um modelo experimental de discinesia tardia no rato. Tese de Mestrado, Escola Paulista de Medicina. São Paulo, 1985.
5. Burt DR, Creese I, Snyder SH. Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 1977, 196:326-328.
6. Cadet JL, Rothman RB. Decreased striatal opiate s-receptors in the rat model of persistent dyskinesia induced by iminodipropionitrille. Neurosci Lett 1986, 72:84-86.
7. Chouza C, Camaño JL, Aljanati R, Scaramellia A, De Medina O, Romero S. Parkinsonism, tardive dyskinesia, akathisia and depression induced by flunarizine. Lancet 1986, 1:1303-1304.
8. Galzin AM, Langer SZ. Presynaptic alpha2-adrenoeeptor antagonism by verapamil but not by dietiazem in rabbit hypothalamic slices. Br J Pharmacol 1983, 78:571-577.
9. Gerlach J. Tardive dyskinesia. Dan, Med Bull 1979, 26:209-245.
10. Goetz CG, Weiner WJ, Nausieda PA, Klawans HL. Tardive dyskinesia: pharmacology and clinical implications. Clin Neuropharmacol 1982, 5:3-22.
11. Grebb JA. Nifedipine and flunarizine block amphetamine-induced behavioral stimulation in mice. Life Sci 1983, 38:2375-2381.
12. Grebb JA, Shelton RC, Freed WJ. Diltiazem or verapamil prevents haloperidol-induced apomorphine supersensitivity in mice. J Neural Transm 1987, 68:241-255.
13. Greenberg DA. Calcium channel antagonists: pharmacology and neurological applications. In Appel SH (ed.) : Current Neurology, Vol. 6. Chicago: Year Book Med Publ, 1986, p 91-121.
14. Hitri A, Weiner WJ, Borison RL. Diamond BI, Nausieda PA, Klawans HL. Dopamine binding following prolonged haloperidol pretreatment. Ann Neurol 1978, 3:134-140.
15. Klawans HL, Rubovitst R. An experimental model of tardive dyskinesia. J Neural Transm. 1972, 33:235-246.
16. Klawans HL, Goetz CG, Carvey P. Animal models of tardive dyskinesias. Clin Neuropharmacol 1983, 6:129-135.
17. Levenson JL, Kennedy K. Dysosmia, dysgeusia and nifedipine. Ann Interm Med 1985, 102:135-136.
18. Melo-Souza, SE. Flunarizina, parkinsonismo e depressão. In Congresso Brasileiro de Neurologia 11ş, Goiânia, 1884: Informações, Programas, Resumos. Goiânia, 1984, p. 39.
19. Meyboom RHB, Ferreira MD, Dieleman BP. Parkinsonism, tardive dyskinesia, akathisia and depression induced by flunarizine. Lancet 1986, 2:292.
20. Micheli F, Pardal MF, Gatto M, Torres M, Paradiso G, Parera IC, Giannaula R. Flunarizine and cinnarizine induced extrapyramidal reactions. Neurology 1987, 37:881-884.
21. Renwart N, Frances H, Simon P. Verapamil s lack of dopaminergic properties in mice. Am J Psychiatry 1986, 143:933-934.
22. Ross JL, Mackenzie TB, Hanson DR, Charles CR. Diltiazem for tardive dyskinesia. Lancet 1987, 1:268.
23. Rubovits R, Klawans HL. Implications of amphetamine-induced stereotyped behavior as a model for tardive dyskinesias. Arch Gen Psychiatry 1972, 27:502-507.
24. Spedding M. Assessment of Ca2+-antagonist effects of drugs in K+-depolarized smooth muscle. Arch Pharmacol 1982, 318:234-240.
25. Spedding M, Cavero I. Calcium antagonists: a class of drugs with a bright future. Part II : Determination of basic pharmacological properties. Life Sci 1984, 35:585-587.
26. Starke K, Spath L, Wichmann T. Effects of verapamil, diltiazem and ryosidine on the release of dopamime and acetylcholine in rabbit cauaate nucleus slices. Arch Pharmacol 1984, 325:124-130.
27. Tepper JM, Groves PM, Young SJ. The neuropharmacology of the autoinhibition of monoamine release. Trends Pharmacol Sci 1985, 6:251-256.
28. Weiner WJ, Carvey P, Nausieda PA, Goetz CG, Klawans HL. Effect of chronic levodopa on haloperidol-induced behavioral supersensitivity in the guinea pig. In Friednoff AJ, Crase TN (eds) : Advances in Neurology, Vol. 35. New York: Raven Press, 1982, p 213-219.