A Possible Relationship Between Folic Acid Neurotoxicity and Cholinergic Receptors in the Pyriform Cortex and Amygdala

  • P. L. McGeer
  • Edith G. McGeer
  • T. Nagai
  • P.-T. Wong
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 18)


The substantia innominata complex (SI) is the major source of cholinergic innervation to the amygdala, entorhinal and pyriform cortices, and the neocortex. Immunohistochemical studies using both monoclonal and polyclonal antibodies to choline acetyltransferase (ChAT) have clearly identified that the large size neurons of this area are cholinergic. We have lesioned this area by three methods: electrocoagulation, kainic acid (KA) injection and folic acid (FA) injection. Biochemical (GAD, ChAT and QNB binding) and histological studies of the SI and its known target areas as well as the hippocampus, thalamus and striatum were undertaken. Histologically, electrolytic and KA (2 nmol) lesions produced extensive local damage, but local damage was minimal with FA (100–250 nmol). Electrolytic lesions produced no remote neuronal damage. KA injections produced mild to moderate damage in the amygdala and cortex, while FA produced severe damage in the amygdala and pyriform cortex, with less severe damage in the entorhinal cortex and neocortex. Biochemically, electrolytic lesions produced drops in ChAT only in remote areas. Kainic acid produced moderate drops in ChAT, GAD and QNB binding. FA, on the other hand, produced only a minimal change in ChAT, but very heavy reductions in GAD and QNB binding. Thus, GABA neurons of the cortex were damaged. They may also be the cholinoceptive neurons that were damaged. The remote damage following KA and, particularly, FA, is presumed to be due to the epileptiform activity induced by the local injection of these agents. Reduction in both seizures and remote damage was brought about by pre-treatment of the animals with valium (20 mg/kg) or scopolamine (50 mg/kg). Injection of FA into the amygdala or striatum produced some remote damage but it was much less in magnitude than after SI injection.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Baylis, E. M., Crowley, J. M., Preece, J. M., Sylvester, P. E., Marks, V.: Influence of folic acid on blood-phenytoin levels. Lancet i, 62–65 (1971).Google Scholar
  2. Ben-Ari, Y., Tremblay, E., Ottersen, O. P., Naquet, R.: Evidence suggesting secondary epileptogenic lesions after kainic acid: pretreatment with diazepam reduces distant but not local brain damage. Brain Res. 165, 362–365 (1979).CrossRefPubMedGoogle Scholar
  3. Ben-Barak,J., Dudai, Y: Early septal lesion: Effect on the development of the cholinergic system in rat hippocampus. Brain Res. 185, 323–334 (1980).CrossRefPubMedGoogle Scholar
  4. Blakely, R. L.: The Biochemistry of Folic Acid and Related Pteridines. (Frontiers of Biology, Vol. 13.) Amsterdam: North-Holland. 1969.Google Scholar
  5. Braestrup, C., Squires, R. F.: Specific benzodiazepine receptors in rat brain characterized by high affinity [3H]diazepam binding. Proc. Natl. Acad. Sci. U.S.A. 74, 3805–3809 (1977).CrossRefPubMedCentralPubMedGoogle Scholar
  6. Braestrup, C., Squires, R.F.: Brain specific benzodiazepine receptors. Brit. J. Psychiat. 133, 149–260 (1978).CrossRefGoogle Scholar
  7. Chanarin, I., Laidlaw,J., Lughridge, L. W., Mollin, D.L.: Megaloblastic anaemia due to phenobarbitone. The convulsant action to therapeutic doses of folic acid. Brit. med. J. i, 1099–1102 (1960).Google Scholar
  8. Cooke, S., Crossland, J.: Effect of short- and long-term administration of some anticonvulsant drugs on the folate content of rat brain. Brit. J. Pharma-col. 64, 407 P (1978).Google Scholar
  9. Davies, J., Watkins, J. R.: Facilitatory and direct excitatory effects of folate and folinate on single neurons of cat cerebral cortex. Biochem. Pharma-col. 22, 1167–1168 (1973).Google Scholar
  10. Goff D., Miller, A. A., Webster, R. A.: Anticonvulsant drugs and folic acid on the development of epileptic kindling in rats. Brit. J. Pharmacol. 64, 406 P (1978).Google Scholar
  11. Hommes, O. R., Obbens, E. A. M. T: The epileptogenic action of sodium folate in the rat. J. neurol. Sci. 16, 271–281 (1972).CrossRefPubMedGoogle Scholar
  12. Houben, P. F. M., Hommes, 0. R., Knaven, P.J. H.: Anti-convulsant drug and folic acid in young mentally retarded epileptic patients. A study of serum folate, fit frequency and I. Q Epilepsia (Amst.) 12, 235–247 (1971).Google Scholar
  13. Hunter, R., Barnes, J., Oakley, H. F., Matthews, D. M.: Toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet i, 61–63 (1970).Google Scholar
  14. Jensen, O. N., Olesen, O. V.: Folic acid and anti-convulsive drugs. Arch. Neurol. Psychiat. (Chic.) 21, 208–214 (1969).CrossRefGoogle Scholar
  15. Kimura, H., Kaneko, Y., Wada, J. A.: Catecholamine and cholinergic systems and amygdala kindling. In: Kindling, Vol. 2 (Wada, J.A., ed.), pp. 265–287. New York: Raven Press. 1981 a.Google Scholar
  16. Kimura, H., McGeer, P. L., Peng, J. H., McGeer, E. G.: The central cholinergic system studied by choline acetyltransferase immunohistochemistry in the cat. J. Comp. Neurol. 200, 151–201 (1981 b).Google Scholar
  17. Konig J. F. R., Klippel, R.A.: The Rat Brain. A Stereotaxic Atlas of the Forebrain and Lower Parts of the Brain Stem. Baltimore: Williams and Wilkins. 1963.Google Scholar
  18. McGeer, E. G., McGeer, P.L.: Some factors influencing the neurotoxicity of intrastriatal injections of kainic acid. Neurochem. Res. 3, 501–517 (1978).CrossRefPubMedGoogle Scholar
  19. McGeer, E. G., Olney, JW, McGeer, P. L. (eds.): Kainic Acid as Tools in Neurobiology. New York: Raven Press. 1978.Google Scholar
  20. McGeer, P. L., McGeer, E. G.: Kainate as a selective lesioning agent. In: Glutamate: Transmitter in the Central Nervous System (Roberts, P.J., StormMathisen, J.,Johnston, G.A.R., eds.), pp. 55–75. New York: J. Wiley. 1981.Google Scholar
  21. McGeer, P. L., Kimura, H., McGeer, E. G., Peng, J. H.: Cholinergic systems in the CNS. In: Compartmentation and Transmitter Interaction (Bradford, H. F., ed.). New York: Plenum Press.Google Scholar
  22. McGeer, P. L., McGeer, E. G., Nagai, T.: GABAergic and cholinergic indices in various regions of rat brain after intracerebral injections of folic acid. Brain Res. 1982 (in press).Google Scholar
  23. Mayersdorf A., Streiff, R.R., Wilder, B.J., Hammer, R. H.: Folic acid and vitamin B12 alterations in primary and secondary epileptic foci induced by metallic cobalt powder. Neurology (Minneap.) 21, 418 (1971).Google Scholar
  24. Nagai, T., Kimura, H., Maeda, T., McGeer, P. L., Peng, F., McGeer, E. G.: Cholinergic projections from the basal forebrain of rat to the amygdala. J. Neurosci. 2, 513–520 (1982).PubMedGoogle Scholar
  25. Olney, J. V., Fuller, T.A., de Gubareff, T.: Kainate-like neurotoxicity of folates. Nature (Lond.) 292, 122–124 (1981).CrossRefGoogle Scholar
  26. Olney, J. V., Fuller, T.A., de Gubare, T., Labruyere, J.: Intrastriatal folic acid mimics the distant but not local brain damage properties of kainic acid. Neurosci. Lett. 25, 185–191 (1981).CrossRefPubMedGoogle Scholar
  27. Price,J. L.: An autoradiographic study of complementary laminar patterns of termination of afferent fibers to the olfactory cortex. J. Comp. Neurol. 150, 87–108 (1973).CrossRefPubMedGoogle Scholar
  28. Ralston, A.J., Snaith, R.P., Hinley, J. B.: Effects of folic acid on fit frequency and behaviour in epileptics on anti-convulsants. Lancet i, 867–868 (1970).Google Scholar
  29. Reynolds, E. H., Chanarin, I., Matthews, D. M.: Neuropsychiatric aspects of anticonvulsant megaloblastic anemia. Lancet i, 394–397 (1968).Google Scholar
  30. Roberts, P.J., Foster, G.A., Thomas, E.M.: Neurotoxic action of methyltetrahydrofolate in rat cerebellum unrelated to direct activation of kainate receptors. Nature (Lond.) 293, 654–655 (1981).CrossRefGoogle Scholar
  31. Ruck, A., Kramer, S., Metz, J., Brennan, M.J. W.: Methyltetrahydrofolate is a potent and selective agonist for kainic acid receptors. Nature (Lond.) 287, 852–853 (1980).CrossRefGoogle Scholar
  32. Takayasu, K., Uchida, S., Noguchi, Y., Fujita, N., Saito, K., Hata, F., Yoshida, H.: Changes in brain muscarinic acetylcholine receptors and behavioural responses to atropine and apomorphine in chronic atropine-treated rats. Life Sci. 25, 585–592 (1979).CrossRefGoogle Scholar
  33. Vincent, S. R., Lehmann, J., McGeer, E. G.: The localization of GABA-trans- aminase in the striato-nigral system. Life Sci. 27, 595–601 (1980).CrossRefPubMedGoogle Scholar
  34. Whitehouse, P.J., Price, D. L., Clark, A. W., Coyle, J. T., DeLong, M. R.: Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann. Neurol. 10, 122–126 (1981).CrossRefPubMedGoogle Scholar
  35. Yamamura, H. I., Snyder, S. H.: Muscarinic cholinergic binding in rat brain. Proc. Natl. Acad. Sci. U.S.A. 71, 1725–1729 (1974 a).Google Scholar
  36. Yamamura, H. I., Snyder, S. H.: Postsynaptic localization of muscarinic cholinergic receptor binding in rat hippocampus. Brain Res. 78, 320–326 (1974 b).Google Scholar

Copyright information

© Springer-Verlag Wien 1983

Authors and Affiliations

  • P. L. McGeer
    • 2
  • Edith G. McGeer
    • 1
  • T. Nagai
    • 2
  • P.-T. Wong
    • 2
  1. 1.Kinsmen Laboratory of Neurological Research, Department of PsychiatryUniversity of British ColumbiaVancouverCanada
  2. 2.Kinsmen Laboratory of Neurological Research, Department of PsychiatryUniversity of British ColumbiaVancouverCanada

Personalised recommendations