, Volume 58, Issue 3, pp 263–269 | Cite as

Effects of chronic lead exposure on levels of acetylcholine and choline and on acetylcholine turnover rate in rat brain areas in vivo

  • Tsung-Ming Shih
  • Israel Hanin


Rats were exposed to lead acetate from birth, and were killed at the age of 44–51 days for analysis of levels and turnover rates of acetylcholine (ACh). Steady-state levels of ACh were not altered in midbrain, cortex, hippocampus, or striatum of lead-exposed rats. Similarly, no changes in choline (Ch) concentrations were found in cortex, hippocampus, or striatum. In the midbrain, however, a 30% reduction in Ch levels was observed. Changes in specific activity of Ch and ACh were measured as a function of time in selected brain areas of rats infused with a radio-labeled precursor of Ch. Specific activities of ACh were not altered. Ch specific activities were, however, significantly elevated in all brain areas examined, as compared with age-matched control rats. The in vivo ACh turnover rate in cortex, hippocampus, midbrain, and striatum was diminished by 35%, 54%, 51% and 33%, respectively. These findings provide direct evidence for an inhibitory effect of lead exposure from birth on central cholinergic function in vivo. Since a significant reduction of body weight was found in those animals treated with lead acetate, the alteration of central cholinergic function may partially be attributed to malnutrition observed in the lead-exposed animals.

Key words

Cholinergic function Acetylcholine Choline Levels Turnover rates Gas chromatography Lead poisoning Malnutrition Central nervous system 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allen, J. R., McWey, P. J., Suomi, S. J.: Pathobiological and behavioral effects of lead intoxication in the infant rhesus monkey. Environ. Health Perspect. 7, 239–246 (1974)Google Scholar
  2. Brown, D. R.: Neonatal lead exposure in the rat: decreased learning as a function of age and blood lead concentrations. Toxicol. Appl. Pharmacol. 32, 628–637 (1975)Google Scholar
  3. Bryan, K. S., Ellison, G.: Cholinergic modulation of an opposed effect of d-amphetamine and methylphenidate on the rearing response. Psychopharmacologia (Berl.) 43, 169–173 (1975)Google Scholar
  4. Carroll, P. T., Silbergeld, E. K., Goldberg, A. M.: Alteration of central cholinergic function by chronic lead acetate exposure. Biochem. Pharmacol. 26, 397–402 (1977)Google Scholar
  5. Clasen, R. A., Hartmann, J. F., Starr, A. J., Coogan, P. S., Pandolfi, S., Laing, I., Becker, R., Hass, G. M.: Electron microscopic and chemical studies of the vascular changes and edema of lead encephalopathy. Am. J Pathol. 74, 215–233 (1974)Google Scholar
  6. David, O., Clark, J., Voeller, K.: Lead and hyperactivity. Lancet 1972 I, 900–903Google Scholar
  7. David, O. J., Hoffman, S. P., Sverd, J., Clark, J., Voeller, K.: Lead and hyperactivity. Behavioral response to chelation: a pilot study. Am. J. Psychiatry 133, 1155–1158 (1976)Google Scholar
  8. De La Burde, B., Choate, M. S. Jr: Does asymptomatic lead exposure in children have latent sequelae. J. Pediatr. 81, 1088–1091 (1972)Google Scholar
  9. Friedman, A. H., Walker, C. A.: The acute toxicity of drugs acting at cholinoceptive sites and twenty-four hour rhythms in brain acetylcholine. Arch. Toxikol. 29, 39–49 (1972)Google Scholar
  10. Golter, M., Michaelson, I. A.: Growth, behavior, and brain catecholamines in lead-exposed neonatal rats: a reappraisal. Science 187, 359–361 (1975)Google Scholar
  11. Grant, L. D., Breese, G., Howard, J. L., Krigman, M. R., Mushak, P.: Neurobiology of lead-intoxication in the developing rat. Fed. Proc. 35, 503 (1976)Google Scholar
  12. Guidotti, A., Cheney, D. L., Trabucchi, M., Doteuchi, M., Wang, C., Hawkins, R. A.: Focussed microwave radiation: a technique to minimize post-mortem changes of cyclic nucleotides, DOPA and choline and to preserve brain morphology. Neuropharmacology 13, 1115–1122 (1974)Google Scholar
  13. Hanin, I., Cheney, D. L., Trabucchi, M., Massarelli, R., Wang, C. T., Costa, E.: Application of principles of steady-state kinetics to measure acetylcholine turnover rate in rat salivary glands: effect of deafferentiation and duct ligation. J. Pharmacol. Exp. Ther. 187:68–77 (1973)Google Scholar
  14. Hanin, I., Costa, E.: Approaches used to estimate brain acetylcholine turnover rate in vivo: effects of drugs on brain acetylcholine turnover rate. In: Biology of cholinergic function. A. M. Goldberg and I. Hanin, eds., pp. 355–377, New York: Raven 1976Google Scholar
  15. Hanin, I., Massarelli, R., Costa, E.: Acetylcholine concentrations in rat brain: diurnal oscillation. Science 170, 341–342 (1970)Google Scholar
  16. Hrdina, P. D., Peters, D. A. V., Sirghal, R. L.: Effects of chronic exposure to cadmium, lead and mercury on brain biogenic amines in the rat. Res. Commun. Chem. Pathol. Pharmacol. 15, 483–493 (1976)Google Scholar
  17. Jason, K., Kellogg, C.: Lead effects on behavioral and neurochemical development in rats. Fed. Proc. 36, 1008 (1977)Google Scholar
  18. Jenden, D. J., Hanin, I.: Gas chromatographic microestimation of choline and acetylcholine after N-demethylation by sodium benenethiolate. In: Choline and acetylcholine: handbook of chemical assay methods. I. Hanin, ed., pp. 135–150. New York: Raven 1974Google Scholar
  19. Kober, T. E., Cooper G. P.: Competitive action of lead and calcium on transmitter release in bullfrog sympathetic ganglia. Fed. Proc. 34, 404 (1975)Google Scholar
  20. Kostial, K., Vouk, V. B.: Lead ions and synaptic transmission in the superior cervical ganglion of the cat. Br. J. Pharmacol. 12, 219–222 (1957)Google Scholar
  21. Krehbiel, D., David, G. A., LeRoy, L. M., Bowman, R. E.: Absence of hyperactivity in lead-exposed developing rats. Environ. Health Perspect. 18, 147–157 (1976)Google Scholar
  22. Krigman, M. R., Druse, M. J., Traylor, T. D., Wilson, M. H., Newell, L. R., Hogan, E. L.: Lead encephalopathy in the developing rat: effect upon myelination. J. Neuropathol. Exp. Neurol. 33, 58–73 (1974)Google Scholar
  23. Landrigan, P. J., Baloh, R. W., Barthel, W. F., Whitworth, R. H., Staehling, N. W., Rosenblum, B. F.: Neuropsychological dysfunction in children with chronic low-level lead absorption. Lancet 1975 I, 708–712Google Scholar
  24. Loch, R., Bornschein, R. L., Michaelson, I. A.: Role of undernutrition in the paradoxical response of lead exposed “hyperactive” mice to amphetamine and phenobarbital. Pharmacologist 18, 124 (1976)Google Scholar
  25. Manalis, R. S., Cooper, G. P.: Presynaptic and postsynaptic effects of lead at the frog neuromuscular junction. Nature 243, 354–356 (1973)Google Scholar
  26. Michaelson, I. A.: Effects of inorganic lead on RNA, DNA and protein content in the developing neonatal rat brain. Toxicol. Appl. Pharmacol. 26, 539–548 (1973)Google Scholar
  27. Michaelson, I. A., Bornschein, R. L., Loch, R. K., Rafales, L. S.: Minimal brain dysfunction hyperkinesis: significance of nutritional status in animal models of hyperactivity. In: Animal models in psychiatry and neurology. I. Hanin and E. Usdin, eds., pp. 37–50, New York: Pergamon 1977Google Scholar
  28. Michaelson, I. A., Greenland R. D., Roth, W.: Increased brain norepinephrine turnover in lead exposed hyperactive rats. Pharmacologist 16, 250 (1974)Google Scholar
  29. Michaelson, I. A., Sauerhoff, M. W.: Animal model of human disease: severe and mild lead encephalopathy in the neonatal rat. Environ. Health Perspect 7, 201–225 (1974)Google Scholar
  30. Millichap, J. G., Fowler, G. W.: Treatment of “minimal brain dysfunction” syndromes: selection of drugs for children with hyperactivity and learning disabilities. Pediatr. Clin. N. Am. 14, 767–777 (1967)Google Scholar
  31. Modak, A. T., Weintraub, S. T., Stavinoha, W. B.: Effect of chronic ingestion of lead on the central cholinergic system in rat brain regions. Toxicol. Appl. Pharmacol. 34, 340–347 (1975)Google Scholar
  32. National Research Council, Committee on the Biological Effects of Atmospheric Pollutants. Lead: airborne lead in perspective. Washington, D.C.: National Academy of Science 1972Google Scholar
  33. Neff, N. H., Spano P. F., Groppetti, A., Wang, C. T., Costa, E.: A simple procedure for calculating the synthesis rate of norepinephrine, dopamine, and serotonin in rat brain. J. Pharmacol. Exp. Ther. 176, 701–710 (1971)Google Scholar
  34. Oberle, M. W.: Lead poisoning: a preventable childhood disease of the slums. Science 165, 991–992 (1969)Google Scholar
  35. Pentschew, A., Garro, F.: Lead encephalo-myelopathy of the suckling rat and its implications on the porphyrinopathic nervous diseases, with special reference to the permeability disorders of the nervous system's capillaries. Acta Neuropathol. 6, 266–278 (1966)Google Scholar
  36. Pepeu, G., Bartolini, A.: Effect of psychoactive drugs on the output of acetylcholine from the cerebral cortex of the cat. Eur. J. Pharmacol. 4, 254–263 (1968)Google Scholar
  37. Perino, J., Ernhart, C. B.: The relation of subclinical lead level to cognitive and sensorimotor impairment in black preschoolers. J. Learn. Disab. 7, 616–620 (1974)Google Scholar
  38. Porges, S. W.: Peripheral and neurochemical parallels of psychopathology: a psychophysiological model relating autonomic imbalance to hyperactivity, psychopathy, and autism. Adv. Child Devel. Behav. 11, 35–63 (1976)Google Scholar
  39. Porges, S. W., Walter, G. F., Korb, R. J., Sprague, R. L.: The influences of methylphenidate on heart rate and behavioral measures of attention in hyperactive children. Child Devel. 46, 727–733 (1975)Google Scholar
  40. Racagni, G., Cheney, D. L., Trabucchi, M., Wang, C., Costa, E.: Measurement of acetylcholine turnover rate in discrete areas of rat brain. Life Sci. 15, 1961–1975 (1974)Google Scholar
  41. Saito, Y., Yamashita, I., Yamazaki, K., Okada, F., Satomi, R., Fujieda, T: Circadian fluctuation of brain acetylcholine in rats. I. On the variations in the total brain and discrete brain areas. Life Sci. 16, 281–288 (1975)Google Scholar
  42. Sauerhoff, M. W., Michaelson, I. A.: Hyperactivity and brain catecholamines in lead-exposed developing rats. Science 182, 1022–1024 (1973)Google Scholar
  43. Schumann, A. M., Dewey, W. L., Borzelleca, J. F., Alphin, R. S.: The effects of lead acetate on central catecholamine function in the postnatal mouse. Fed. Proc. 36, 405 (1977)Google Scholar
  44. Shih, T.-M., Khachaturian, Z. S., Barry, H., III: Evidence for cholinergically mediated effect of methylphenidate hydrochloride in the central nervous system. Pharmacologist 16, 242 (1974)Google Scholar
  45. Shih, T.-M., Khachaturian, Z. S., Barry, H., III, Hanin, I.: Cholinergic mediation of the inhibitory effect of methylphenidate on neuronal activity in the reticular formation. Neuropharmacology 15, 55–60 (1976)Google Scholar
  46. Shih, T.-M., Khachaturian, Z. S., Hanin, I.: Involvement of both cholinergic and catecholaminergic pathways in the central action of methylphenidate: a study utilizing lead-exposed rats. Psychopharmacology 55, 187–193 (1977)Google Scholar
  47. Silbergeld, E. K., Carroll, P. T., Goldberg, A. M.: Monoamines in lead-induced hyperactivity. Pharmacologist 17, 212 (1975)Google Scholar
  48. Silbergeld, E. K., Chisolm, J. J. Jr: Lead poisoning: altered urinary catecholamine metabolites as indicators of intoxication in mice and children. Science 192, 153–155 (1976)Google Scholar
  49. Silbergeld, E. K., Fales, J. T., Goldberg, A. M.: The effects of inorganic lead on the neuromuscular junction. Neuropharmacology 13, 795–801 (1974)Google Scholar
  50. Silbergeld, E. K., Goldberg, A. M.: A lead-induced behavioral disorder. Life Sci. 13, 1275–1283 (1973)Google Scholar
  51. Silbergeld, E. K., Goldberg, A. M.: Lead-induced behavioral dysfunction: an animal model of hyperactivity. Exp. Neurol. 42, 146–157 (1974a)Google Scholar
  52. Silbergeld, E. K., Goldberg, A. M.: Cholinergic-aminergic interactions in lead-induced hyperactivity. Pharmacologist 16, 249 (1974b)Google Scholar
  53. Silbergeld, E. K., Goldberg, A. M.: Pharmacological and neurochemical investigations of lead-induced hyperactivity. Neuropharmacology 14, 431–444 (1975)Google Scholar
  54. Silbergeld, E. K., Goldberg, A. M.: Hyperactivity. In: Biology of cholinergic function. A. M. Goldberg and I. Hanin, eds., pp. 619–645. New York: Raven 1976Google Scholar
  55. Snowdon, C. T.: Learning deficits in lead-ingested rats. Pharmacol. Biochem. Behav. 1, 599–604 (1973)Google Scholar
  56. Sobotka, T. J., Brodie, R. E., Cook, M. P.: Psychophysiologic effects of early lead exposure. Toxicology 5, 175–191 (1975)Google Scholar
  57. Sobotka, T. J., Cook, M. P.: Postnatal lead acetate exposure in rats: possible relationship to minimal brain dysfunction. Am. J. Ment. Defic. 79, 5–9 (1974)Google Scholar
  58. Stavinoha, W. B., Weintraub, S. T., Modak, A. T.: The use of microwave heating to inactive cholinesterase in the rat brain prior to analysis for acetylcholine. J Neurochem. 20, 361–371 (1973)Google Scholar
  59. Werry, J. S.: Developmental hyperactivity. Pediatr. Clin. N. Am. 15, 581–599 (1968)Google Scholar
  60. Wessel, M. A., Dominski, A.: Our children's daily lead. Am. Sci. 65, 294–298 (1977)Google Scholar
  61. Wince, L. C., Donovan, C. H., Azzaro, A. J.: Behavioral and biochemical analysis of the lead-exposed hyperactive rat. Pharmacologist 18, 198 (1976)Google Scholar

Copyright information

© Springer-Verlag 1978

Authors and Affiliations

  • Tsung-Ming Shih
    • 1
  • Israel Hanin
    • 1
  1. 1.Department of Psychiatry, Western Psychiatric Institute and ClinicUniversity of Pittsburgh School of MedicinePittsburgh

Personalised recommendations