Olney (1) found not only hypothalamic lesions in 1969, but described stunted skeletal development, obesity, and female sterility, as well as a spate of observed pathological changes found in several brain regions associated with endocrine function in maturing mice which had been given glutamic acid (GLU) as neonates.
Longitudinal studies in which neonatal/infant animals were given doses of GLU and then observed over a period of time before being sacrificed for brain examination, repeatedly supported Olney's early findings of abnormal development, behavioral aberration, and neuroendocrine disorder.(1)
Developmental dysfunction or abnormalities in growth and behavior have been noted in numbers of animal studies. Animals treated with GLU as neonates or in the first 12 days of life suffer neuroendocrine disturbances including obesity and stunting, abnormalities of the reproductive system, and underdevelopment of certain endocrine glands (1-22) and possible learning deficits either immediately or in later life (8,11-12,23-29).
In addition, Bhagavan and others have reported behavioral reactions including somnolence and seizures (30-37); tail automutilation (10,24); and learned taste aversion.(26) Irritability to touch was interpreted as conspicuous emotional change by Nemeroff.(10) Lynch reported hyperglycemia along with growth suppression. He noted that hyperglycemia did not occur when subjects were given intact protein containing a large amount of GLU.(38)
Olney et al. have written a number of review articles which summarize
the data on neuroendocrine dysfunction following GLU treatment.(39-41)
Nemeroff has provided another.(42)
1. Olney, J.W. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164: 719-721, 1969
2. Lamperti, A., and Blaha, G. The effects of neonatally-administered monosodium glutamate on the reproductive system of adult hamsters. Biol Reprod 14: 362-369, 1976.
3. Holzwarth-McBride, M.A., Hurst, E.M., and Knigge, K.M. Monosodium glutamate induced lesions of the arcuate nucleus. I. Endocrine deficiency and ultrastructure of the median eminence. Anat Rec 186: 185-196, 1976.
4. Lemkey-Johnston, N., and Reynolds, W.A. Nature and extent of brain lesions in mice related to ingestion of monosodium glutamate: a light and electron microscope study. J Neuropath Exp Neurol 33: 74-97, 1974.
5. Matsuyama, S. Studies on experimental obesity in mice treated with MSG. Jap J Vet Sci 32: 206, 1970.
6. Redding, T.W., Schally, A.V., Arimura, A., and Wakabayashi, I. Effect of monosodium glutamate on some endocrine functions. Neuroendocrinology 8: 245-255, 1971.
7. Knittle, J.L., Ginsberg-Fellner, F. Cellular and metabolic alterations in obese rats treated with monosodium glutamate during the neonatal period. Program and Abstracts of the American Pediatric Society Atlantic City, New Jersey, April 29, 1970, p6. or Bulletin Am Peds Soc Gen Mtg Program Abstracts p 6, April 1970.
8. Araujo, P.E., and Mayer J. Activity increase associated with obesity induced by monosodium glutamate in mice. Am J Physiol 225: 764-765, 1973.
9. Nagasawa, H., Yanai R., and Kikuyama, S. Irreversible inhibition of pituitary prolactin and growth hormone secretion and of mammary gland development in mice by monosodium glutamate administered neonatally. Acta Endocrinol 75: 249-259, 1974.
10. Nemeroff, C.B., Grant, L.D., Bissette, G., Ervin, G.N., Harrell, L.E., and Prange, A.J., Jr. Growth, endocrinological and behavioral deficits after monosodium L-glutamate in the neonatal rat: Possible involvement of arcuate dopamine neuron damage. Psychoneuroendocrinology 2: 179-196, 1977.
11. Nemeroff, C.B., Konkol, R.J., Bissette, G., Youngblood, W., Martin, J.B., Brazeau, P., Rone, M.S., Prange, A.J. Jr., Breese, G.R. and Kizer, J.S. Analysis of the disruption in hypothalamic-pituitary regulation in rats treated neonatally with monosodium glutamate (MSG): Evidence for the involvement of tuberoinfundibular cholinergic and dopaminergic systems in neuroendocrine regulation. Endocrinology 101: 613-622, 1977.
12. Pizzi, W.J., Barnhart, J.E., and Fanslow, D.J. Monosodium glutamate administration to the newborn reduces reproductive ability in female and male mice. Science 196: 452-454, 1977.
13. Tafelski, T.J. and Lamperti, A.A. The effects of a single injection of monosodium glutamate on the reproductive neuroendocrine axis of the female hamster. Biol Reprod 17: 404-411, 1977.
14. Takasaki, Y, Sekine, S., Matsuzawa, Y., Iwata, S., and Sasaoka, M. Effects of parenteral and oral administration of monosodium L-glutamate (MSG) on somatic growth in rats. Toxicol Lett 4: 327-343, 1979.
15. Matsuzawa, Y., Yonetani, S., Takasaki, Y., Iwata, S., and Sekine, S. Studies on reproductive endocrine function in rats treated with monosodium L-glutamate early in life. Toxicol Lett 4: 359-371, 1979.
16. Matsuyama, S., Oki,Y., and Yokoki, Y. Obesity induced by monosodium glutamate in mice. Natl Inst Anim Health Q (Tokyo) 13: 91-101, 1973.
17. Pizzi, W.J., and Barnhart, J.E. Effects of monosodium glutamate on somatic development, obesity and activity in the mouse. Pharmacol Biochem Behav 5: 551-557, 1976.
18. Nikoletseas, M.M. Obesity in exercising, hypophagic rats treated with monosodium glutamate. Physiol Behav 19: 767-773, 1977.
19. Redding, T.W., and Schally, A.V. Effect of monosodium glutamate on the endocrine axis in rats. Fed Proc Fed Am Soc Exp Biol 29: 378A (abstract #755), 1970.
20. Holzwarth, M.A., and Hurst, E.M. Manifestations of monosodium glutamate (MSG) induced lesions of the arcuate nucleus of the mouse. Anat Rec 178: 378, 1974.
21. Trentini, G.P., Botticelli, A., and Botticelli, C.S. Effect of monosodium glutamate on the endocrine glands and on the reproductive function of the rat. Fertil Steril 25: 478-483, 1974.
22. Lynch, J.F. Jr., Lewis, L.M., Hove, E.L., and Adkins, J.S. Division of Nutrition, FDA, Washington, D.C. 20204. Effect of monosodium L-glutamate on development and reproduction in rats. Fed Proc 29: 567Abs, 1970.
23. Pradhan, S.N., Lynch, J.F., Jr. Behavioral changes in adult rats treated with monosodium glutamate in the neonatal state. Arch Int Pharmacodyn Ther 197: 301-304, 1972.
24. Iwata, S., Ichimura, M., Matsuzawa, Y., Takasaki, Y., and Sasaoka, M. Behavioral studies in rats treated with monosodium L-glutamate during the early states of life. Toxicol Lett 4: 345-357, 1979.
25. Vorhees, C.V., Butcher, R.E., Brunner, R.L., and Sobotka, T.J. A developmental test batter for neurobehavioral toxicity in rats: a preliminary analysis using monosodium glutamate, calcium carrageenan, and hydroxyurea. Toxicol Appl Pharm 50: 267-282, 1979.
26 Vogel, J.R., and Nathan, B.A. Learned taste aversions induced by high doses of monosodium L-glutamate. Pharmacol Biochem Behav 3: 935-937, 1975.
27. Berry, H.K., and Butcher, R.E. Biochemical and behavioral effects of administration of monosodium glutamate to the young rat. Soc Neurosci 3rd Ann Mtg. S.D. 5/8/1973.
28. Berry, H.K., Butcher, R.E., Elliot, L.A., and Brunner, R.L. The effect of monosodium glutamate on the early biochemical and behavioral development of the rat. Devl Psychobiol 7: 165-173, 1974.
29. Weiss, L.R., Reilly, J.F., Williams, J., and Krop, S. Effects of prolonged monosodium glutamate and other high salt diets on arterial pressure and learning ability in rats. Toxicol Appl Pharmacol 19: 389, 1971.
30. Bhagavan, H.N., Coursin, D.B., and Stewart, C.N. Monosodium glutamate induces convulsive disorders in rats. Nature (London) 232: 275-276, 1971.
31. Johnston, G.A.R. Convulsions induced in 10-day-old rats by intraperitoneal injection of monosodium glutamate and related excitant amino acids. Biochem Pharmacol 22: 137-140, 1973.
32. Mushahwar, I.K. and Koeppe, R.E. The toxicity of monosodium glutamate in young rats. Biochem Biophys Acta 244: 318-321, 1971.
33. Nemeroff, C.B., and Crisley, F.D. Lack of protection by pyridoxine or hydrazine pretreatment against monosodium glutamate induced seizures. Pharmacol Biochem Behav 3: 927-929, 1975.
34. Nemeroff, C.B., and Crisley, F.D. Monosodium L-glutamate induced convulsions: temporary alteration in blood-brain barrier permeability to plasma proteins. Environ Physiol Biochem 5: 389-395, 1975.
35. Wiechert, P. Gollinitz, G. Metabolic investigations of epileptic seizures: the activity of the glutamate decarboxylase prior to and during experimentally produced convulsions. J Neurochem 15: 1265-1270, 1968. (Abstract)
36. Wiechert, P., and Herbst, A. Provocation of cerebral seizures by derangement of the natural balance between glutamic acid and y-aminobutyric acid. J Neurochem 13: 59-64, 1966.
37. Wiechert, P., and Gollnitz, G. Metabolic investigations of epileptic seizures: investigations of glutamate metabolism in regions of the dog brain in preconvulsive states. J Neurochem 17: 137-147, 1970. (Abstract)
38. Lynch, J.F., Jr., Lewis, L.M., and Adkins, J.S. (Division of Nutrition, FDA, Washington, D.C. 20204). Monosodium glutamate-induced hyperglycemia in weanling rats. J S Fed Proc 31: 1477, 1971.
39. Olney, J.W. and Price, M.T. Neuroendocrine interactions of excitatory and inhibitory amino acids. Brain Research Bulletin 5: Suppl 2, 361-368, 1980.
40. Olney, J.W. and Price M.T. Excitotoxic amino acids as neuroendocrine probes. In: Kainic Acid as a Tool in Neurobiology McGeer, E.G., et al. Eds. New York: Raven Press, 1978.
41. Olney, J.W. Excitotoxic amino acids: research applications and safety implications. In: Glutamic Acid: Advances in Biochemistry and Physiology Filer, L.J. Jr., et al. Ed. New York: Raven Press, 1979.
42. Nemeroff, C.B. Monosodium glutamate-induced neurotoxicity: review
of the literature and call for further research. In: Nutrition & Behavior
Miller, S.A., Ed. Philadelphia: The Franklin Institute Press, 1981.
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