Skip to main content
SpringerLink
Log in

Effect of chronic administration of phenytoin on regional monoamine levels in rat brain

  • Original Articles
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Phenytoin (DPH) is a widely used anticonvulsant drug but a conclusive mode of action is not yet clear. This study was undertaken to assess the effects of chronic administration of DPH on monoamine levels. DPH (50 mg/kg body weight) was administered to adult male Wistar rats by intraperitoneal injections for 45 days and the regional brain levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were assayed using high performance liquid chromatographic (HPLC) method. The experimental rats revealed no behavioral deficits of any kind nor body and brain weight deficits were observed. Increased NE levels were observed after DPH administration in motor cortex (P<0.05), striatum-accumbens (P<0.01) and hippocampus (P<0.01), whereas, NE level was decreased in brain stem (P<0.05). DA levels were increased in striatum-accumbens (P<0.05), hypothalamus (P<0.001) and cerebellum (P<0.001) but decreased in brainstem (P<0.01). In DPH treated rats, 5-HT levels were increased in motor cortex (P<0.001) but decreased in cerebellum (P<0.001) when compared to control group of rats. The present study suggest that chronic administration of DPH induces alterations in monoamine levels in specific brain regions. DPH seems to mediate, its anticonvulsant action by selectively altering the monoamine levels in different brain regions.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Perry, J. G., McKinney, L., and Dewier, P. 1978. The cellular mode of action of the antiepileptic drug 5,5 diphenylhydantoin. Nature (Lond.) 272:271–273.

    Google Scholar 

  2. DeLorenzo, R. J., and Glaser, G. H. 1976. Effect of diphenyl hydantoin on the endogenous phosphorylation of brain protein. Brain Res. 105:381–386.

    PubMed  Google Scholar 

  3. Yaari, Y., Selzer, M. E., and Pincus, J. H. 1986. Phenytoin: Mechanisms of its anticonvulsant action. Ann. Neurol. 20:171–184.

    PubMed  Google Scholar 

  4. Lewin, E., and Bleck, V. 1971. The effect of diphenylhydantoin administration on cortex potassium—activated phosphatase. Neurology 21:417–418.

    Google Scholar 

  5. De Weer, P. 1980. Phenytoin blockage of resting sodium channels. Adv. Neurol. 27:253–261.

    Google Scholar 

  6. Ondrusek, M. G., Belknap, J. K., and Leslie, S. W. 1979. Effects of acute and chronic barbiturate administration on synaptosomal calcium accumulation. Mol. Pharmacol. 15:386–395.

    PubMed  Google Scholar 

  7. Brouillette, W. J., Brown, G. B., Delorey, T. M., and Liang, G. 1990. Sodium channel binding and anticonvulsant activities of hydantoins containing conformationally constrained 5-phenyl substituents. J. Pharmacol. Sci. 79:871–874.

    Google Scholar 

  8. Woodbury, D. M. 1982. Phenytoin: mechanism of action. Pages 269–282,in Woodbury, D. M., Penry, J. K. and Pippenger C. E. (eds.), Antiepileptic drugs second edition, Raven Press, New York.

    Google Scholar 

  9. Ito, S., Nakazato, Y., and Ohga, A. 1978. Pharmacological evidence for the involvement of Na+ channels in the release of catocholamines from perfused adrenal glands. Brit. J. Pharmacol. 62:359–361.

    Google Scholar 

  10. Kilpatrick, D. L., Slepetis, R., and Kirshner, N. 1981. Ion channels and membrane potential in stimulus secretion coupling in adrenal medulla cells. J. Neurochem. 36:1245–1255.

    PubMed  Google Scholar 

  11. Jones, G. L., and Woodbury, D. M. 1985. Biochemistry of antiepileptic drugs. Pages 254–268.in Frey H. H. and Janz D. (eds) Handbook of experimental pharmacology. Vol. 74, Springer-Verlag, Berlin.

    Google Scholar 

  12. Reynolds, E. H. 1983. Mental effects of antiepileptic medication. A review. Epilepsia 24 (Suppl. 2):85–95.

    Google Scholar 

  13. Quattrone, A., Crunelli, V., and Samanin, R. 1978. Seizure susceptibility and anticonvulsant activity of carbamazepine, diphenylhydantoin and phenobarbital in rats with selective depletions of brain monoamines. Neuropharmacol. 17:643–647.

    Google Scholar 

  14. Waldmeier, P. C., Baumann, P. A., Fehr, B., De Herdt, P., and Maitre, L. 1984. Carbamazepine decreases catecholamine turnover in the rat brain. J. Pharmacol. Exp. Ther. 231:166–172.

    PubMed  Google Scholar 

  15. Devinsky, O., Emoto, S., Goldstein, D. S., Stull, R., Porter, R. J., Theoder, W. H., and Suzan Nadi, N. et al., 1992. Cerebrospinal fluid and serum levels of Dopa, catechols and monoamine metabolites in patients with epilepsy. Epilepsia 33:263–270.

    PubMed  Google Scholar 

  16. Lindgren, S., Anden, N. E., and Anden, M. G. 1982. A Flourometric method for determination of GABA in tissue following cation exchange chromatography and condensation with Ophthalaldehyde. J. Neural Transm 55:243–252.

    Google Scholar 

  17. Meshkibaf, M. H., Subhash, M. N., Lakshmana, M. K., and Rama Rao, B. S. S. 1994. Sodium Valproate induced alteration in monoamine levels in different regions of the rat brain, Neurochemistry Int. 24:67–72.

    Google Scholar 

  18. Masuda, Y., Utsuim, Y., Shiraishi, Y., Karasava, T., Yoshida, K., and Shimizu, M. 1979. Relationships between plasma concentrations of diphenylhydantoin, phenobarbital, carbamazepine, and 3-sulfomoyl-methyl-1,2 benzisozaxole (AD-810), a new anticonvulsant agent and their anticonvulsant or neurotoxic effects in experimental animals. Epilepsia 20:623–633.

    PubMed  Google Scholar 

  19. DeLorenzo, R. J. 1980. Phenytoin: Calcium and calmodulin dependent protein phosphorylation and neurotransmitter release. Pages 56–71,in Glaser, G. H., Penry, J. K. and Woodbury D. M. (eds.), Antiepileptic drugs: Mechanisms of action Raven Press, New York.

    Google Scholar 

  20. Pincus, J. H., and Weinfeld, H. M. 1984. Effect of phenytoin on3H norepinephrine release from synaptosomes. Brain Res. 348:387–390.

    Google Scholar 

  21. Boer, T. H., Stoof, J. C., and Duijn H. V. 1982. The effects of convulsant and anticonvulsant drugs on the release of radiolabeled GABA, glutamate, noradrenaline, serotonin and acetylcholine from rat cortical slices. Brain Res. 253:153–160.

    PubMed  Google Scholar 

  22. Trottier, S., Berger, B., Chanvel, P., Dedek, J., and Gay, M. 1981. Alterations of the cortical noradrenergic systems in chronic cobalt epileptogenic foci in the rat: A histofluorescent and biochemical study. Neuroscience 6:1069–1080.

    PubMed  Google Scholar 

  23. Remler, M. P., Sigvardt, K., and Marcussen, W. H. 1986. Pharmacological response of systematically derived focal epileptic lesions. Can. Med. Assoc. J. 74:365–366.

    Google Scholar 

  24. Jobe, P., Laird, H., Ko, K. H., Ray, T., and Dailey, J. W. et al. 1982. Abnormalities in monoamine levels in the central nervous system of the genetically epilepsy prone rats. Epilepsia 23:359–366.

    PubMed  Google Scholar 

  25. Altamura, A. C., Bonati, M., Brunello, N., Giardano, P. L., and Algori, S. et al., 1978. The activity of some neurotransmitter synthesizing enzymes in experimental cobalt epilepsy. Neuroscience Lett. 7:83–87.

    Google Scholar 

  26. Elliott, P. N., Jenner, P., and Chadwick, O. 1977. The effect of diphenylhydantoin on central catecholamine containing neuronal systems. J. Pharm. Pharmacol., 29:41–43.

    PubMed  Google Scholar 

  27. Quattrone, A., Annunziato, L., Aguglia, U., and Preziosi, P. 1981. Carbamazepine, phenytoin and phenobarbitone do not influence brain catecholamine uptake, invivo in male rats. Arch. Int. Pharmacodynam. Ther. 252:180–185.

    Google Scholar 

  28. Yanagihara, T., and Hamberger, A. 1971. Distribution of diphenyl-hydantoin in rat organs: Study with neuron, glia and subcellular fractions. J. Pharmacol. Exp. Ther. 179:611–618.

    PubMed  Google Scholar 

  29. De Lima, T. C. M., and Palermo, Neto. J. 1980. The effects of diphenyl hydantoin on rat behaviour. Psychopharmacology (Berlin) 69:183–185.

    Google Scholar 

  30. Lalonde, R. 1985. Dopaminergic supersensitivity after long term administration of phenytoin in the rats. Epilepsia. 26:81–84.

    PubMed  Google Scholar 

  31. Mori, A., Hiramatsu, M., and Namha, S. 1987. Decreased dopamine level in the epileptic focus. Res. Commun. Chem. Pathol. Pharmacol. 56:157–164.

    PubMed  Google Scholar 

  32. Laird, H. 1983. Abnormal concentrations and turnover rates of norepinephrine and dopamine in brains of genetically seizure-susceptible rats. Epilepsia 24:107–113.

    Google Scholar 

  33. Bernardi, G., Chenubini, E., Marciani, M. G., and Mercuri, N. 1982. Responses of intracellular recorded cortical neurons to the iontophoretic application of dopamine. Brain Res. 245:267–274.

    PubMed  Google Scholar 

  34. Stanzione, P., Galabresi, P., Mercuri, N. and Bernardi, G. 1984. Dopamine modulates CA1 hippocampal neurons by elevating the threshold for spike generation, an invitro study. Neuroscience 13:1105–1116.

    PubMed  Google Scholar 

  35. Bonnycastle, D. D., Bonny, Castle, M. F., and Anderson, E. G. 1962. The effect of a number of central depressant drugs upon brain 5-hydroxytryptamine levels in the rat. J. Pharmacol. Exp. Ther. 196:469–475.

    Google Scholar 

  36. Chadwick, D., Jenner, P., and Reynolds, E. H. 1975 Amines, anticonvulsants and epilepsy. Lancet 1:473–476.

    PubMed  Google Scholar 

  37. Azzaro, A. J., Gutrecht J. A., and Smith, D. J. 1973. Effect of diphenylhydantoin on the uptake and catabolism of L-(3H)-norepinephrine in vitro in rat cerebral cortex tissue. Biochem. Pharmacol. 22:2719–2724.

    PubMed  Google Scholar 

  38. Fry, B. W., and Ciarlone, A. E. 1981. Effect of phenytoin on mouse cerebellar 5-hydroxy tryptamine and norepinephrine. Neuropharmacology 20:623–625.

    PubMed  Google Scholar 

  39. Goldstein, D., Nadi, N. S., and Stull, R. 1988. Levels of catechols in normal and epileptic regions of the human brain. J. Neurochem. 50:225–229.

    PubMed  Google Scholar 

  40. Schreiber, R. A., and Schlesinger, K. 1971. Circadian rhythms and seizure susceptibility: relation to serotonin and norepinephrine in brain. Physiol. Behav. 6:635–640.

    PubMed  Google Scholar 

  41. Pintor, M., Pocotte, S., Mefford, I., and Indols, 1988. Catechol and tryosine hydroxylase in the human epileptic cortex. Soc. Neurosci. Abstr. 14:1032.

    Google Scholar 

  42. Mac Donald, J. W., Garofalo, E. A., Hood, J., Sackellares, J. C., Gilman, S., McKeever, P. E., Troncoso, J. C., and Johnston, M. V. 1991. Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy. Ann. Neurol. 29:529–541.

    PubMed  Google Scholar 

  43. Cavalheiro, E. A., Fernandes, M. J., Turski, L., and Naffah-Mazzacoratti, M. G. 1994. Spontaneous recurrent seizures in rats: amino acid and monoamine determination in the hippocampus. Epilepsia 35:1–11.

    Google Scholar 

  44. Green J. R., Halpern, L. M., Thomas, Jr. E. D., and Amick-Corkill, J. A. 1978. The effect of diphenylhydantoin on the activity of selected enzymes in chronic isolated cerebral cortex of rat. Epilepsia 14:223–232.

    Google Scholar 

  45. Meshki Baf, M. H., Subhash, M. N., Lakshmana, M. K., and Sridhara Rama Rao, B. S. 1994. Alterations in monoamine levels in discrete regions of rat brain after chronic administration carbamazepine. Neurochem. Res. 19:1137–1141.

    Google Scholar 

  46. Meshki Baf, M. H., Subhash, M. M., Lakshmana, M. K., and Sridhara Rama Rao, B. S. 1994. Alterations in brain regional monoamine levels after chronic administration of phenobarbitone to adult rats. Biogenic Amines 10:213–219.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurochemistry, National Institute of Mental Health and Neurosciences, 560 029, Bangalore, India

    M. H. Meshkibaf (Additional Professor), M. N. Subhash (Additional Professor) & B. S. Sridhara Rama Rao

  2. Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Bangalore, India

    K. Madepalli Lakshmana

Authors
  1. M. H. Meshkibaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. N. Subhash
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Madepalli Lakshmana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. S. Sridhara Rama Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meshkibaf, M.H., Subhash, M.N., Lakshmana, K.M. et al. Effect of chronic administration of phenytoin on regional monoamine levels in rat brain. Neurochem Res 20, 773–778 (1995). https://doi.org/10.1007/BF00969688

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00969688

Key Words

Search

Navigation