Abstract
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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
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)
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)
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)
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)
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)
David, O., Clark, J., Voeller, K.: Lead and hyperactivity. Lancet 1972 I, 900–903
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)
De La Burde, B., Choate, M. S. Jr: Does asymptomatic lead exposure in children have latent sequelae. J. Pediatr. 81, 1088–1091 (1972)
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)
Golter, M., Michaelson, I. A.: Growth, behavior, and brain catecholamines in lead-exposed neonatal rats: a reappraisal. Science 187, 359–361 (1975)
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)
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)
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)
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 1976
Hanin, I., Massarelli, R., Costa, E.: Acetylcholine concentrations in rat brain: diurnal oscillation. Science 170, 341–342 (1970)
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)
Jason, K., Kellogg, C.: Lead effects on behavioral and neurochemical development in rats. Fed. Proc. 36, 1008 (1977)
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 1974
Kober, T. E., Cooper G. P.: Competitive action of lead and calcium on transmitter release in bullfrog sympathetic ganglia. Fed. Proc. 34, 404 (1975)
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)
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)
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)
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, 708–712
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)
Manalis, R. S., Cooper, G. P.: Presynaptic and postsynaptic effects of lead at the frog neuromuscular junction. Nature 243, 354–356 (1973)
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)
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 1977
Michaelson, I. A., Greenland R. D., Roth, W.: Increased brain norepinephrine turnover in lead exposed hyperactive rats. Pharmacologist 16, 250 (1974)
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)
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)
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)
National Research Council, Committee on the Biological Effects of Atmospheric Pollutants. Lead: airborne lead in perspective. Washington, D.C.: National Academy of Science 1972
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)
Oberle, M. W.: Lead poisoning: a preventable childhood disease of the slums. Science 165, 991–992 (1969)
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)
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)
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)
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)
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)
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)
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)
Sauerhoff, M. W., Michaelson, I. A.: Hyperactivity and brain catecholamines in lead-exposed developing rats. Science 182, 1022–1024 (1973)
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)
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)
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)
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)
Silbergeld, E. K., Carroll, P. T., Goldberg, A. M.: Monoamines in lead-induced hyperactivity. Pharmacologist 17, 212 (1975)
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)
Silbergeld, E. K., Fales, J. T., Goldberg, A. M.: The effects of inorganic lead on the neuromuscular junction. Neuropharmacology 13, 795–801 (1974)
Silbergeld, E. K., Goldberg, A. M.: A lead-induced behavioral disorder. Life Sci. 13, 1275–1283 (1973)
Silbergeld, E. K., Goldberg, A. M.: Lead-induced behavioral dysfunction: an animal model of hyperactivity. Exp. Neurol. 42, 146–157 (1974a)
Silbergeld, E. K., Goldberg, A. M.: Cholinergic-aminergic interactions in lead-induced hyperactivity. Pharmacologist 16, 249 (1974b)
Silbergeld, E. K., Goldberg, A. M.: Pharmacological and neurochemical investigations of lead-induced hyperactivity. Neuropharmacology 14, 431–444 (1975)
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 1976
Snowdon, C. T.: Learning deficits in lead-ingested rats. Pharmacol. Biochem. Behav. 1, 599–604 (1973)
Sobotka, T. J., Brodie, R. E., Cook, M. P.: Psychophysiologic effects of early lead exposure. Toxicology 5, 175–191 (1975)
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)
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)
Werry, J. S.: Developmental hyperactivity. Pediatr. Clin. N. Am. 15, 581–599 (1968)
Wessel, M. A., Dominski, A.: Our children's daily lead. Am. Sci. 65, 294–298 (1977)
Wince, L. C., Donovan, C. H., Azzaro, A. J.: Behavioral and biochemical analysis of the lead-exposed hyperactive rat. Pharmacologist 18, 198 (1976)
Author information
Authors and Affiliations
Additional information
Part of this work was presented in abstract form (Fed. Proc. 36. 977 (1977))
Rights and permissions
About this article
Cite this article
Shih, TM., Hanin, I. Effects of chronic lead exposure on levels of acetylcholine and choline and on acetylcholine turnover rate in rat brain areas in vivo. Psychopharmacology 58, 263–269 (1978). https://doi.org/10.1007/BF00427389
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00427389