An Antioxidant Neuroprotectant and Extracellular Neuromodulator
  • George V. Rebec


Ascorbic acid, which exists primarily as the ascorbate anion at physiological pH, participates in many life-sustaining functions. It is perhaps best known as a cofactor in the synthesis of collagen, a connective-tissue protein (Englard and Seifter, 1986), but ascorbate also promotes iron absorption, regulates cholesterol synthesis and elimination, and generally seems essential for the normal operation of all bodily organs (Navas et al., 1994; Meister, 1992; Tolbert, 1985). This versatility arises from a redox potential of +0.080, which allows ascorbate to donate reducing equivalents to many different compounds (Niki, 1991; Bendich et al., 1986; Halliwell and Gutteridge, 1985). In fact, its role as a highly efficient reducing agent confers another critical function on ascorbate: neutralizing toxic free radicals formed during oxidative metabolism (Beyer, 1994; Rose and Bode, 1993; Sies et al., 1992).


Ascorbic Acid Basal Ganglion Dopamine Receptor Dopamine Agonist Tardive Dyskinesia 
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  1. Adams, J. D., and Odunze, I. N., 1991, Oxygen free radicals and Parkinson’s disease, Free Rad. Biol. Med. 10(2):161–169.PubMedGoogle Scholar
  2. Alexander, G. E., and Crutcher, M. D., 1990, Functional architecture of basal ganglia circuits: neural substrates of parallel processing, Tr. Neurosci. 13:266–271.Google Scholar
  3. Bach-y-Rita, P., 1993, Neurotransmission in the brain by diffusion through the extracellular fluid—a review, Neuroreport 4(4):343–350.PubMedGoogle Scholar
  4. Barja, G., Lopeztorres, M., Perezcampo, R., Rojas, C., Cadenas, S., Prat, J., and Pamplona, R., 1994, Dietary vitamin C decreases endogenous protein oxidative damage, malondialdehyde, and lipid peroxidation and maintains fatty acid unsaturation in the guinea pig liver, Free Rad. Biol. Med. 17(2): 105–115.PubMedGoogle Scholar
  5. Basse-Tomusk, A., and Rebec, G. V. (1990), Corticostriatal and thalamic regulation of amphetamine-induced ascorbate release in the neostriatum, Pharmacol. Biochem. Behav. 35:55–60.PubMedGoogle Scholar
  6. Basse-Tomusk, A., and Rebec, G. V., 1991, Regional distribution of ascorbate and 3,4-dihydroxyphenylace-tic acid (DOPAC) in rat neostriatum, Brain Res. 538:29–35.PubMedGoogle Scholar
  7. Bendich, A., Machlin, L. J., Scandurra, O., Burton, G. W., and Wayner, D. D. M., 1986, The antioxidant role of vitamin C., Adv. Free Rad. Biol. Med. 2:419–444.Google Scholar
  8. Ben-Shachar, D., and Youdim, M. B. H., 1993, Iron, melanin and dopamine interaction—relevance to Parkinson’s disease, Prog. Neuro-Psychopharmacol. Biol. Psychiai. 17(1): 139–150.Google Scholar
  9. Beyer, R. E., 1994, The role of ascorbate in antioxidant protection of biomembranes: Interaction with vitamin E and coenzyme Q, J. Bioenerget. Biomemb. 26(4):349–358.Google Scholar
  10. Bigge, C. F., and Boxer, P. A., 1994, Neuronal cell death and strategies for neuroprotection, Annu. Rep. Med. Chem. 29:13–22.Google Scholar
  11. Blunt, S. B., Jenner, P., and Marsden, C. D., 1993, Suppressive effect of L-dopa on dopamine cells remaining in the ventral tegmental area of rats previously exposed to the neurotoxin 6-hydroxydopamine, Mov. Disord. 8:129–133.PubMedGoogle Scholar
  12. Bonorden, W. R., and Pariza, M. W., 1994, Antioxidant nutrients and protection from free radicals, in: Nutritional Toxicology (F. N. Kotsonis, M. Mackey, J. Hjelle, eds.), Raven Press, New York, pp. 19–48.Google Scholar
  13. Boutelle, M. G., Svensson, L., and Fillenz, M., 1989, Rapid changes in striatal ascorbate in response to tailpinch monitored by constant potential voltammetry, Neuroscience 30:11–17.PubMedGoogle Scholar
  14. Cadet, J. L., and Kahler, L. A., 1994, Free radical mechanisms in schizophrenia and tardive dyskinesia, Neurosci. Biobehav. Rev. 18(4):457–467.PubMedGoogle Scholar
  15. Cammack, J., Ghasemzadeh, B., and Adams, R. N., 1991, The pharmacological profile of glutamate-evoked ascorbic acid efflux measured by in vivo electrochemistry, Brain Res. 565(1): 17–22.PubMedGoogle Scholar
  16. Carlsson, M., and Carlsson, A., 1990, Interactions between glutamatergic and monoaminergic systems within the basal ganglia: implications for schizophrenia and Parkinson’s disease, Tr. Neurosci. 13:272–276.Google Scholar
  17. Chakraborty, S., Nandi, A., Mukhopadhyay, M., Mukhopadhyay, C. K., and Chatterjee, I. B., 1994, Ascorbate protects guinea pig tissues against lipid peroxidation, Free Rad. Biol. Med. 16:417–426.PubMedGoogle Scholar
  18. Chiueh, C. C., Miyake, H., and Peng, M.-T., 1993, Role of dopamine autoxidation, hydroxyl radical generation, and calcium overload in underlying mechanisms involved in MPTP-induced parkinsonism, in: Advances in Neurology, Volume 60, (H. Narabayashi, T. Nagatsu, N. Yanagisawa, and Y. Mizuno, eds.), Raven Press, New York, pp. 251–258.Google Scholar
  19. Choi, D. W., 1992, Excitotoxic cell death, J. Neurobiol. 23:1261–1276.PubMedGoogle Scholar
  20. Christensen, E., Moller, J. E., and Faurbye, A., 1970, Neuropathological investigation of 28 brains from patients with dyskinesia Acta Psychiatr. Scand. 46:14–23.PubMedGoogle Scholar
  21. Christensen, J. R. C., and Rebec, G. V., 1994, Further evidence for control of neostriatal ascorbate release via a nigro-thalamo-corticoneostriatal loop, Soc. Neurosci. Abstr. 20:732.Google Scholar
  22. Clemens, J. A., and Phebus, L. A., 1984, Brain dialysis in conscious rats confirms in vivo electrochemical evidence that dopaminergic stimulation releases ascorbate, Life Sci. 35:671–677.PubMedGoogle Scholar
  23. Coyle, J. T., and Puttfarcken, P., 1993, Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695.PubMedGoogle Scholar
  24. Dalgalarrondo, P., and Gattaz, W. F., 1994, Basal ganglia abnormalities in tardive dyskinesia—and possible relationships with duration of neuroleptic treatment, Eur. Arch. Psychiatr. Clin. Neurosci. 244:272–277.Google Scholar
  25. Desole, M. S., Anania, V., Esposito, G., Carboni, F., Senini, A., and Miele, E., 1987, Neurochemical and behavioural changes induced by ascorbic acid and d-amphetamine in the rat, Pharmacol. Res. Commun. 19:441–450.PubMedGoogle Scholar
  26. Desole, M. S., Miele, M., Enrico, P., Fresu, L., Esposito, G., Denatale, G., and Miele, E., 1992, The effects of cortical ablation on d-amphetamine-induced changes in striatal dopamine turnover and ascorbic acid catabolism in the rat, Neurosci. Lett. 139:29–33.PubMedGoogle Scholar
  27. DeVito, M. J., and Wagner, G. C., 1989, Methamphetamine-induced neuronal damage: A possible role for free radicals, Neuropharmacology 28(10): 1145–1150.Google Scholar
  28. Dexter, D. T., Carter, C. J., Wells, F. R., Javoy-Agid, F., Agid, Y, Lees, A., Jenner, P., Marsden, C. D., 1989, Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease, J. Neurochem. 52:381–389.PubMedGoogle Scholar
  29. Dexter, D. T., Jenner, P., Schapira, A. H. V., and Marsden, C. D., 1992, Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia, Ann. Neurol. 32(suppl.):S94-S100.Google Scholar
  30. Dugan, L. L., and Choi, D. W, 1994, Excitotoxicity, free radicals, and cell membrane changes, Ann. Neurol. 35:S17-S21.Google Scholar
  31. Dunnett, S. B., and Robbins, T. W, 1992, The functional role of mesotelencephalic dopamine systems, Biol. Rev. Cambridge Philosophical Soc. 67(4):491–518.Google Scholar
  32. Duvoisin, R. C., 1991, Diseases of the extrapyramidal system, in: Comprehensive Neurology (R. N. Rosenberg, ed.), Raven Press, New York, pp. 337–364.Google Scholar
  33. Ebersole, B. J., and Molinoff, P. B., 1991, Inhibition of binding of PN200–110 to membranes from rat brain and heart by ascorbate is mediated by lipid peroxidation, J. Pharmacol. Exp. Therap. 9(1):337–344.Google Scholar
  34. Ellenbroek, B. A., 1993, Treatment of schizophrenia—a clinical and preclinical evaluation of neuroleptic drugs, Pharmac Ther. 57(1): 1–78.Google Scholar
  35. Englard, S., and Seifter, S., 1986, The biochemical functions of ascorbic acid, Annu. Rev. Nutr. 6:365–406.PubMedGoogle Scholar
  36. Ewing, A. G., Alloway, K. D., Curtis, S. D., Dayton, M. A., Wightman, R. M., and Rebec, G. V., 1983, Simultaneous electrochemical and unit recording measurements: characterization of the effects of d-amphetamine and ascorbic acid on neostriatal neurons, Brain Res. 261:101–108.PubMedGoogle Scholar
  37. Fahn, S., 1991, An open trial of high-dosage antioxidants in early Parkinson’s disease, Am. J. Clin. Nutr. 53(1):S380-S382.Google Scholar
  38. Fahn, S., and Cohen, G., 1992, The oxidant stress hypothesis in Parkinson’s disease-evidence supporting it, Ann. Neurol. 32(6):804–812.PubMedGoogle Scholar
  39. Fallon, J. H., 1988, Topographic organization of ascending dopaminergic projections, Ann. NY Acad. Sci., 537:1–9.PubMedGoogle Scholar
  40. Fernandez-Calle, P., Jimenez-Jimenez, F J., Molina, J. A., Cabreravaldivia, F., Vazquez, A., Urra, D. G., Bermejo, F, Matallana, M. C., and Codoceo, R., 1993, Serum levels of ascorbic acid (vitamin-C) in patients with Parkinson’s disease, J. Neurolog. Sci. 118:25–28.Google Scholar
  41. Fibiger, H. C., and Lloyd K. G., 1984, Neurobiological substrates of tardive dyskinesia: The GABA hypothesis. Tr. Neurosci. 7:462–464.Google Scholar
  42. Fillenz, M., O’Neill, R. D., and Grunewald, R. A., 1986, Changes in extracellular brain ascorbate concentration as an index of excitatory aminoacid release, in: Monitoring Neurotransmitter Release During Behaviour (M. H. Joseph, M. Fillenz, I. A. MacDonald, and C. A. Marsden, eds.) Ellis Norwood, Chichester, England, pp. 144–163.Google Scholar
  43. Fornstedt, B., and Carlsson, A., 1991, Vitamin-C deficiency facilitates 5-S-cysteinyldopamine formation in guinea pig striatum, J. Neurochem. 56:407–414.PubMedGoogle Scholar
  44. Freed, W. J., 1989, An hypothesis regarding the antipsychotic effect of neuroleptic drugs, Pharmacol. Biochem. Behav. 32:337–345.PubMedGoogle Scholar
  45. Frei, B., 1991, Ascorbic acid protects lipids in human plasma and low-density lipoprotein against oxidative damage, Am. J. Clin. Nutr. 54:S 1113—S1118.Google Scholar
  46. Fuxe, K., and Agnati, L. F, 1991, Two principal modes of electrochemical communication in the brain—volume versus wiring transmission, Vol. Transm. Brain 1:1–9.Google Scholar
  47. Garcia-Bunuel, L., and Garcia-Bunuel, V. M., 1965, Cerebrospinal fluid levels of free myoinositol in some neurological disorders. Neurology 15:348–350.PubMedGoogle Scholar
  48. Gardiner, T. W., Armstrong-James, M., Caan, A. W., Wightman, R. M., and Rebec, G. V., 1985, Modulation of neostriatal unit activity by iontophoresis of ascorbic acid, Brain Res. 344:181–185.PubMedGoogle Scholar
  49. Ghasemzedah, B., Cammack, J., and Adams, R. N., 1991, Dynamic changes in extracellular fluid ascorbic acid monitored by in vivo electrochemistry, Brain Res. 547(1): 162–166.PubMedGoogle Scholar
  50. Giannini, A. J., Loiselle, R. H., DiMarzio, L. R., and Giannini, M. C., 1987, Augmentation of haloperidol by ascorbic acid in phencyclidine intoxication. Am. J. Psychiat. 144:1207–1209.PubMedGoogle Scholar
  51. Gibb, J. W., Hanson, G. R., and Johnson, M., 1994, neurochemical mechanisms of toxicity, in: Amphetamine and Its Analogs (A. K. Cho, and D. S. Segal, eds.), Academic Press, San Diego, pp. 269–295.Google Scholar
  52. Gonon, F, Buda, M., Cespuglio, R., Jouvet, M., and Pujol, J. F, 1981, Voltammetry in the striatum of chronic freely moving rats: detection of catechols and ascorbic acid, Brain Res. 223:69–80.PubMedGoogle Scholar
  53. Götz, M. E., Kunig, G., Riederer, P., and Youdim, M. B. H., 1994, Oxidative stress: Free radical production in neural degeneration, Pharmacol. Therap. 63(1):37–122.Google Scholar
  54. Grace, A. A., 1991, Phasic versus tonic dopamine release and the modulation of dopamine system responsivity—a hypothesis for the etiology of schizophrenia, Neuroscience 41(1): 1–24.PubMedGoogle Scholar
  55. Groves, P. M., Rebec, G. V., and Harvey, J. A., 1975, Alteration of the effects of (+)-amphetamine on neuronal activity in the striatum following lesions of the nigrostriatal bundle, Neuropharmacology 14:369–376.PubMedGoogle Scholar
  56. Grunewald, R. A., 1993, Ascorbic acid in the brain, Brain Res. Rev. 18(1):123–133.PubMedGoogle Scholar
  57. Grunewald, R. A., and Fillenz, M., 1984, Release of ascorbate from synaptosomal fraction of rat brain, Neurochem. Int. 6:491–500.PubMedGoogle Scholar
  58. Gulley, J. M., and Rebec, G. V., 1995, Dose-dependent effects of ascorbate on conditioned avoidance response, Soc. Neurosci. Abstr. 21:2088.Google Scholar
  59. Hadjiconstantinou, M., and Neff, N. H., 1983, Ascorbic acid could be hazardous to your experiments: a commentary on dopamine receptor binding studies with speculation on a role for ascorbic acid in neuronal function, Neuropharmacology 22:939–943.PubMedGoogle Scholar
  60. Hall, E. D., and Braughler, J. M., 1993, Free radicals in CNS injury, in: Molecular and Cellular Approaches to the Treatment of Neurological Disease (S. G. Waxman, ed.), Raven Press, New York, pp. 81–105.Google Scholar
  61. Halliwell, B., and Gutteridge, J. M. C., 1985, Free Radicals in Biology and Medicine, Clarendon, Oxford.Google Scholar
  62. Halliwell, B., Gutteridge, J. M. C., and Cross, C. E., 1992, Free radical, antioxidants, and human disease: Where are we now?, J. Lab. Clin. Med. 119:598–620.PubMedGoogle Scholar
  63. Haracz, J. L., Tschanz, J. T., Wang, Z., White, I. M., and Rebec, G. V., 1993, Striatal single-unit responses to amphetamine and neuroleptics in freely moving rats, Neurosci. Biobehav. Rev. 17:1–12.PubMedGoogle Scholar
  64. Hastings, T. G., and Zigmond, M. J., 1994, Identification of catechol-protein conjugates in neostriatal slices incubated with [H-3]dopamine: Impact of ascorbic acid and glutathione, J. Neurochem. 63(3): 1126–1132.PubMedGoogle Scholar
  65. Heikkila, R. E., Cabbat, F. S., and Manzino, L., 1981, Differential inhibitory effects of ascorbic acid on the binding of dopamine agonists and antagonists to neostriatal membrane preparations: correlations with behavioral effects, Res. Commun. Chem. Path. Pharmacol. 34:409–421.Google Scholar
  66. Heimer, L., Zahm, D. S., and Alheid, G. F, 1995, Basal ganglia, in: The Rat Nervous System, 2nd Edition, (G. Paxinos, ed.), Academic Press, San Diego, pp. 579–628.Google Scholar
  67. Herrling, P. L., 1985, Pharmacology of the corticocaudate excitatory postsynaptic potential in the cat: Evidence for its mediation by quisqualate- or kainate-receptors, Neuroscience 14(2):417–426.PubMedGoogle Scholar
  68. Hillered, L., Persson, L., Bolander, H. G., Hallström, Å., and Ungerstedt, U., 1988, Increased levels of ascorbate in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis, Neurosci. Lett. 95:286–290.PubMedGoogle Scholar
  69. Hughes, R. E., Hurley, R. J., and Jones, P. R., 1971, The retention of ascorbic acid by guinea pig tissues. Brit. J. Nutr. 26:433–438.PubMedGoogle Scholar
  70. Irwin, I., 1986, The neurotoxin 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP): A key to Parkinson’s disease? Pharmac. Res. 3(1):7–11.Google Scholar
  71. Jackson, D. M., and Westlind-Danielsson, A., 1994, Dopamine receptors: molecular biology, biochemistry and behavioural aspects, Pharmacol. Therap. 64(2):291–370.Google Scholar
  72. Jellinger, K., 1986, Pathology of parkinsonism, in: Recent Developments in Parkinsons Disease (S. Fahn et al., eds.), Raven Press, New York, pp. 33–66.Google Scholar
  73. Jenner, P., 1993, Altered mitochondrial function, iron metabolism and glutathione levels in parkinson’s disease, Acta Neurol. Scand. 87(Suppl. 146):6–13.Google Scholar
  74. Jenner, P., Dexter, D. T., Sian, J., Schapira, A. H. V., and Marsden, C. D., 1992, Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incidental lewy body disease, Ann. Neurol. 32(Suppl.):S82-S87.Google Scholar
  75. Jeste, D. V., and Wyatt, R. J., 1981, Dogma disputed: Is tardive dyskinesia due to postsynaptic dopamine receptor supersensitivity? J. Clin. Psychiat. 42:455–157.Google Scholar
  76. Kamata, K., and Rebec, G. V., 1985, Nigral reticulata neurons: Potentiation of responsiveness to amphetamine with long-term treatment, Brain Res. 332:188–193.PubMedGoogle Scholar
  77. Kamata, K., Wilson, R. L., Alloway, K. D., and Rebec, G. V., 1986, Multiple amphetamine injections reduce the release of ascorbic acid in the neostriatum of the rat, Brain Res. 362:331–338.PubMedGoogle Scholar
  78. Kanai, Y., Smith, C. P., and Hediger, M. A., 1994, A new family of neurotransmitter transporters: the high-affinity glutamate transporters, FASEB J. 8:1450–1459.Google Scholar
  79. Kaufmann, P., Wiens, W, Dirks, M., and Krehbiel, D., 1986, Changes in social behavior and brain catecholamines during the development of ascorbate deficiency in guinea pigs, Behav. Processes 13:13–28.Google Scholar
  80. Kiely, M. E., Lai, S., and Vasavan Nair, N. P., 1987, effect of ascorbic acid on brain amphetamine concentrations in the rat, Prog. Neuro-Psychopharmacol. Biol. Psychiat. 11:287–290.Google Scholar
  81. Kimura, K., and Sidhu, A., 1994, Ascorbic acid inhibits I-125-SCH 23982 binding but increases the affinity of dopamine for D-l dopamine receptors, J. Neurochem. 63(6):2093–2098.PubMedGoogle Scholar
  82. Kiyatkin, E. A., and Rebec, G. V., 1996, Dopaminergic modulation of glutamate-induced excitations of neurons in the neostriatum and nucleus accumbens of awake, unrestrained rats, J. Neurophy. 75:142–153.Google Scholar
  83. Klausner, J. D., Sweeney, J. A., Deck, M. D. E, Haas, G. L., and Kelly, A. B., 1992, Clinical correlates of cerebral ventricular enlargement in schizophrenia—further evidence for frontal lobe disease, J. Nerv. Ment. Dis. 180(7):407–412.PubMedGoogle Scholar
  84. Kuo, C.-H., Hata, F., Yoshida, H., Yamatodani, A., and Wada, H., 1979, Effect of ascorbic acid on release of acetylcholine from synaptic vesicles prepared from different species of animals and release of noradrenaline from synaptic vesicles of rat brain, Life Sci. 24:911–915.PubMedGoogle Scholar
  85. Langston, J. W., Irwin, I., and Ricaurte, G. A., 1987, Neurotoxins, parkinsonism and Parkinson’s disease, Pharmac. Therap. 32:19–49.Google Scholar
  86. Layer, R. T., Bland, L. R., and Skolnick, P., 1993, MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity, Brain Res. 625(1):38–44.PubMedGoogle Scholar
  87. Liang, N. Y, and Rutledge, C. O., 1982, Comparison of the release of [3H]dopamine from isolated corpus striatum by amphetamine, fenfluramine and unlabelled dopamine, Biochem. Pharm. 31:983–992.PubMedGoogle Scholar
  88. Lieberman, J. A., and Koreen, A. R., 1993, Neurochemistry and neuroendocrinology of schizophrenia—a selective review, Schizophrenia Bull. 19(2):371–429.Google Scholar
  89. Louilot, A., Gonon, E, Buda, M., Simon, H., Le Moal, M., and Pujol, J. E, 1985, Effects of d- and l-amphetamine on dopamine metabolism and ascorbic acid levels in nucleus accumbens and olfactory tubercle as studied by in vivo differential pulse voltammetry, Brain Res. 336:253–263.PubMedGoogle Scholar
  90. Majewska, M. D., Bell, J. A., and London, E. D., 1990, Regulation of the NMD A receptor by redox phenomena—inhibitory role of ascorbate, Brain Res. 537(1–2):328–332.PubMedGoogle Scholar
  91. Marshall, J. E, Odell, S. J., and Weihmuller, F. B., 1993, Dopamine-glutamate interactions in methamphet-amine-induced neurotoxicity, J. Neural Trans. 91:(2–3):241–254.Google Scholar
  92. McIlwain, H., Thomas, J., and Bell, J. L., 1956, The composition of isolated cerebral tissues: ascorbic acid and cozymase, Biochem. J. 64:332–335.PubMedGoogle Scholar
  93. Mefford, I. N., Oke, A. F., and Adams, R. N., 1981, Regional distribution of ascorbate in human brain, Brain Res. 212:223–226.PubMedGoogle Scholar
  94. Meister, A., 1992, On the antioxidant effects of ascorbic acid and glutathione, Biochem. Pharmacol. 44(10):1905–1915.PubMedGoogle Scholar
  95. Meltzer, H. Y., and Nash, J. F., 1991, Effects of antipsychotic drugs on serotonin receptors, VII, Pharmacolog. Rev. 43(4):587–604.Google Scholar
  96. Milby, K., Oke, A., and Adams, R. N., 1982, Detailed mapping of ascorbate distribution in rat brain, Neurosci. Lett. 28:169–174.PubMedGoogle Scholar
  97. Miller, R., and Chouinard, G., 1993, Loss of striatal cholinergic neurons as a basis for tardive and L-dopa- induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia, Biol. Psychiat. 34:713–738.PubMedGoogle Scholar
  98. Montgomery, E. B., 1995, Heavy metals and the etiology of Parkinson’s disease and other movement disorders, Toxicology 97(1–3):3–9.PubMedGoogle Scholar
  99. Mueller, K., 1989, Repeated administration of high doses of amphetamine increases release of ascorbic acid in caudate but not nucleus accumbens, Brain Res. 494:30–35.PubMedGoogle Scholar
  100. Mueller, K., 1990, The effects of haloperidol and amphetamine on ascorbic acid and uric acid in caudate and nucleus accumbens of rats as measured by voltammetry in vivo, Life Sci. 47:735–742.PubMedGoogle Scholar
  101. Mueller, K., and Haskett, C., 1987, Effects of haloperidol on amphetamine-induced increases in ascorbic acid as determined by voltammetry in vivo, Pharmacol. Biochem. Behav. 27:231–234.PubMedGoogle Scholar
  102. Mueller, K., and Kunko, P. M., 1990, The effects of amphetamine and pilocarpine on the release of ascorbic and uric acid in several brain areas, Pharmacol. Biochem. Behav. 35:871–876.PubMedGoogle Scholar
  103. Navas, P., Villalba, J. M., and Cordoba, F., 1994, Ascorbate function at the plasma membrane, Biochim. Biophy. Acta Rev. Biomemb. 1197(1):1–13.Google Scholar
  104. Niki, E., 1991, Action of ascorbic acid as a scavenger of active and stable oxygen radicals, Am. J. Clin. Nutr. 54(6):S1119-S1124.Google Scholar
  105. O’Dell, S. J., Weihmuller, F. B., and Marshall, J. F, 1991, Multiple methamphetamine injections induce marked increases in extracellular striatal dopamine which correlate with subsequent neurotoxicity, Brain Res. 564(2):256–260.PubMedGoogle Scholar
  106. O’Dell, S. J., Weihmuller, F. B., and Marshall, J. F., 1993, Methamphetamine-induced dopamine overflow and injury to striatal dopamine terminals—attenuation by dopamine D(l) or D(2) antagonists. J. Neurochem. 60(5): 1792–1799.PubMedGoogle Scholar
  107. Oh, C., Gardiner, T. W., and Rebec, G. V, 1989, Blockade of both D1- and D2-dopamine receptors inhibits amphetamine-induced ascorbate release in the neostriatum, Brain Res. 480:184–189.PubMedGoogle Scholar
  108. Ohmori, T., Koyama, T., Muraki, A., Yamashita, I., 1993, Competitive and noncompetitive N-Methyl- D-aspartate antagonists protect dopaminergic and serotonergic neurotoxicity produced by methamphetamine in various brain regions, J. Neural Transm. 92(2–3):97–106.Google Scholar
  109. Oke, A. F., May, L., and Adams, R. N., 1987, Ascorbic acid distribution patterns in human brain, in: Third Conference on Vitamin C., Annals of the New York Academy of Sciences, Volume 498 (J. J. Burns, J. M. Rivers, and L. J. Machlin, eds.), New York Academy of Sciences, New York, pp. 1–12.Google Scholar
  110. O’Neill, R., 1995, The measurement of brain ascorbate in vivo and its link with excitatory amino acid neurotransmission, in: Voltammetric Methods in Brain Systems, Neuromethods, Volume 27 (A. Boulton, G. Baker, R. N. Adams, eds.), Humana Press, Clifton, New Jersey, pp. 221–268.Google Scholar
  111. O’Neill, R. D., Fillenz, M., and Albery, W. J., 1982, Circadian changes in homovanillic acid and ascorbate levels in the rat striatum using microprocessor-controlled voltammetry, Neurosci. Lett. 34:189–193.PubMedGoogle Scholar
  112. O’Neill, R. D., Grunewald, R. A., Fillenz, M., and Albery, W. J., 1983, The effect of unilateral cortical lesions on the circadian changes in rat striatal ascorbate and homovanillic acid levels measured in vivo using voltammetry, Neurosci. Lett. 42:105–110.PubMedGoogle Scholar
  113. O’Neill, R. D., Fillenz, M., Sundstrom, L., and Rawlins, J. N. P., 1984, Voltammetrically monitored brain ascorbate as an index of excitatory amino acid release in the unrestrained rat, Neurosc. Lett. 52:227–233.Google Scholar
  114. Pardo, B., Mena, M. A., Casarejos, M. J., Paino, C. L., and Deyebenes, J. G., 1995, Toxic effects of L-DOPA on mesencephalic cell cultures: Protection with antioxidants, Brain Res. 682(1–2): 133–143.PubMedGoogle Scholar
  115. Parent, A., Cote, P. Y, and Lavoie, B., 1995, Chemical anatomy of primate basal ganglia, Prog. Neurobiol. 46:131–197.PubMedGoogle Scholar
  116. Phebus, L. A., Roush, M. E., and Clemens, J. A., 1990, Effect of direct and indirect dopamine agonists on brain extracellular ascorbate levels in the striatum and nucleus accumbens of awake rats, Life Sci. 47:1317–1323.PubMedGoogle Scholar
  117. Pierce, R. C., and Rebec, G. V., 1990, Stimulation of both Dl and D2 dopamine receptors increases behavioral activation and ascorbate release in the neostriatum of freely moving rats, Eur. J. Pharmacol. 191:295–302.PubMedGoogle Scholar
  118. Pierce, R. C., and Rebec, G. V., 1992, Dopamine-, NMD A-, and sigma-receptor antagonists exert differential effects on neostriatal ascorbate and DOPAC in awake, behaving rats, Brain Res. 579:59–66.PubMedGoogle Scholar
  119. Pierce, R. C., and Rebec, G. V., 1993, Intraneostriatal administration of glutamate antagonists increases behavioral activation and decreases neostriatal ascorbate via non-dopaminergic mechanisms, J. Neuro-sci. 13:4272–4280.Google Scholar
  120. Pierce, R. C., and Rebec, G. V., 1995, Iontophoresis in the neostriatum of awake, unrestrained rats: differential effects of dopamine, glutamate, and ascorbate on motor- and nonmotor-related neurons, Neuroscience 67:313–324.PubMedGoogle Scholar
  121. Pierce, R. C., Rowlett, J. K., Bardo, M. T., and Rebec, G. V., 1991, Chronic ascorbate potentiates the effects of chronic haloperidol on behavioral supersensitivity but not D2 dopamine receptor bindings, Neuroscience 45:373–378.PubMedGoogle Scholar
  122. Pierce, R. C., Miller, D. M., Reising, D., and Rebec, G. V., 1992, Unilateral neostriatal kainate, but not 6-OHDA lesions, block dopamine agonist-induced ascorbate release in the neostriatum of freely-moving rats, Brain Res. 597:138–143.PubMedGoogle Scholar
  123. Pierce, R. C., Clemens, A. J., Grabner, C. P., and Rebec, G. V., 1994a, Amphetamine promotes neostriatal ascorbate release via a nigro-thalamo-corticoneostriatal loop, J. Neurochem. 63:1499–1507.PubMedGoogle Scholar
  124. Pierce, R. C., Clemens, A. J., Shapiro, L. A., and Rebec, G. V., 1994b, Repeated treatment with ascorbate or haloperidol, but not clozapine, elevates extracellular ascorbate in the neostriatum of freely moving rats, Psychopha rmacology 116:103–109.Google Scholar
  125. Pierce, R. C., Rowlett, J. K., Rebec, G. V., and Bardo, M. T., 1995, Ascorbate potentiates amphetamine-induced conditioned place preference and forebrain dopamine release in rats, Brain Res. 688:21–26.PubMedGoogle Scholar
  126. Poirier, J., and Thiffault, C., 1993, Are free radicals involved in the pathogenesis of idiopathic Parkinson’s disease?, Eur. Neurol. 33(Suppl. l):38–43.PubMedGoogle Scholar
  127. Raiteri, M., Cerrito, F., Cervoni, A. M., and Levi, G., 1979, Dopamine can be released by two mechanisms differentially affected by the dopamine transport inhibitor nomifensine, J. Pharm. Exp. Then 208:195–202.Google Scholar
  128. Rebec, G. V., and Bashore, T. R., 1984, Critical issues in assessing the behavioral effects of amphetamine, Neurosci. Biobehav. Rev. 8:153–159.PubMedGoogle Scholar
  129. Rebec, G. V., and Groves, P. M., 1975, Apparent feedback from the caudate nucleus to the substantia nigra following amphetamine administration, Neuropharmacology 14:275–282.PubMedGoogle Scholar
  130. Rebec, G. V., and Pierce, R. C., 1994, A vitamin as neuromodulator: Ascorbate release into the extracellular fluid of the brain regulates dopaminergic and glutamatergic transmission, Prog. Neurobiol. 43:537–565.PubMedGoogle Scholar
  131. Rebec, G. V., Centore, J. M., White, L. K., and Alloway, K. D., 1985, Ascorbic acid and the behavioral response to haloperidol: Implications for the action of antipsychotic drugs, Science 227:438–440.PubMedGoogle Scholar
  132. Rebec, G. V., Wightman, R. M., Fillenz, M., Heikkila, R. E., Gardiner, T. W., and Adams, R. N., 1986, Ascorbate: a vitamin as neuromodulator, Soc. Neurosci. Abstr. 12:170.Google Scholar
  133. Reiter, R. J., 1995, Oxidative processes and antioxidative defense mechanisms in the aging brain, FASEB J. 9(7):526–533.PubMedGoogle Scholar
  134. Ricaurte, G. A., Sabol, K. E., Seiden, L. S., 1994, Functional Consequences of Neurotoxic Amphetamine Exposure, in: Amphetamine and Its Analogs (A. K. Cho and D. S. Segal, eds.), Academic Press, San Diego, pp. 297–313.Google Scholar
  135. Rice, M. E., and Cammack, J., 1991, Anoxia-resistant turtle brain maintains ascorbic acid content in vitro, Neurosci. Lett. 132(2): 141–145.PubMedGoogle Scholar
  136. Rice, M. E., and Nicholson, C., 1987, Interstitial ascorbate in turtle brain is modulated by release and extracellular volume change, J. Neurochem. 49:1096–1104.PubMedGoogle Scholar
  137. Riederer, P., Sofic, E., Rausch, W.-D., Schmidt, B., Reynolds, G. P., Jellinger, K., and Youdim, M. B. H., 1989, Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52:515–520.PubMedGoogle Scholar
  138. Rollema, H., Skolnik, M., Dengelbronner, J., Igarashi, K., Usuki, E., and Castagnoli, N., 1994, MPP(+)-like neurotoxicity of a pyridinium metabolite derived from haloperidol—in vivo microdialysis and in vitro mitochondrial studies, J. Pharmacol Exp. Therap. 268(1):380–387.Google Scholar
  139. Rose, R. C., and Bode, A. M., 1993, Biology of free radical scavengers—An evaluation of ascorbate, FASEB J. 7(12):1135–1142.PubMedGoogle Scholar
  140. Rupniak, N. M. J., Jenner, P., and Marsden, C. D., 1983, The effect of chronic neuroleptic administration on cerebral dopamine receptor function, Life Sci. 32:2289–2311.PubMedGoogle Scholar
  141. Schenk, J. O., Miller, E., Gaddis, R., and Adams, R. N., 1982, Homeostatic control of ascorbate concentration in CNS extracellular fluid, Brain Res. 253:353–356.PubMedGoogle Scholar
  142. Schmidt, C., and Gibb, J., 1985, Role of the dopamine uptake carrier in the neurochemical response to methamphetamine: Effects of amfonelic acid, Eur. J. Pharmacol. 109:73–80.PubMedGoogle Scholar
  143. Schulz, D. W., Lewis, M. H., Petitto, J., and Mailman, R. B., 1984, Ascorbic acid decreases [3H]dopamine binding in striatum without inhibiting dopamine-sensitive adenylate cyclase, Neurochem. Int. 6:117–121.PubMedGoogle Scholar
  144. Seeman, P., 1992, Dopamine receptor sequences—therapeutic levels of neuroleptics occupy D2-receptors, clozapine occupies D4, Neuropsychopharmacology 7(4):261–284.PubMedGoogle Scholar
  145. Segal, D. S., and Janowsky, D. S., 1978, Psychostimulant-induced behavioral effects: Possible models of schizophrenia, in: Psychopharmacology: A Generation of Progress (M. A. Lipton, A. DiMascio, and K. F. Killam, eds.), Raven Press, New York, pp. 1113–1123.Google Scholar
  146. Seiden, L., and Vosmer, G., 1984, Formation of 6-hydroxydopamine in caudate nucleus of the rat brain after a single large dose of methamphetamine, Pharmacol. Biochem. Behav. 21:29–31.PubMedGoogle Scholar
  147. Seiden, L. S., Sabol, K. E., Ricaurte, G. A., 1993, Amphetamine—effects on catecholamine systems and behavior, Annu. Rev. Pharmacol. Toxicol. 33:639–677.PubMedGoogle Scholar
  148. Shivakumar, B. R., and Ravindranath, V., 1992, Oxidative stress induced by administration of the neuroleptic drug haloperidol is attenuated by higher doses of haloperidol, Brain Res. 595:256–262.PubMedGoogle Scholar
  149. Sies, H., Stahl, W., and Sundquist, A. R., 1992, Antioxidant functions of vitamins—vitamin E and vitamin C, beta-carotene, and other carotenoids, in: Beyond Deficiency, Volume 669, Annals of the New York Academy of Sciences, (H. E. Säuberlich, and L. J. Machlin, eds.), New York Academy of Sciences, New York, pp. 7–20.Google Scholar
  150. Sonsalla, P. K., Riordan, D. E., and Heikkila, R. E., 1991, Competitive and noncompetitive antagonists at N-Methyl-D-aspartate receptors protect against methamphetamine-induced dopaminergic damage in mice, J. Pharmacol. Exp. Ther. 256(2):506–512.PubMedGoogle Scholar
  151. Sonsalla, P. K., Gibb, J. W., and Hanson, G. R., 1986, Roles of Dl and D2 dopamine receptor subtypes in mediating the methamphetamine-induced changes in monoamine systems, J. Pharmacol. Exp. Ther. 238:932–937.PubMedGoogle Scholar
  152. Spector, R., 1981, Penetration of ascorbic acid from cerebrospinal fluid into brain, Exp. Neurol. 72:645–653.PubMedGoogle Scholar
  153. Spector, R., 1989, Micronutrient homeostasis in mammalian brain and cerebrospinal fluid, J. Neurochem. 53:1667–1674.PubMedGoogle Scholar
  154. Spector, R., and Lorenzo, A. V., 1974, Specificity of ascorbic acid transport system of the central nervous system, Am. J. Physiol. 226:1468–1473.PubMedGoogle Scholar
  155. Stadtman, E. R., 1991, Ascorbic acid and oxidative inactivation of proteins. Am. J. Clin. Nutr. 54(6):S1125-S1128.Google Scholar
  156. Stamford, J. A., Kruk, Z. L., and Millar, J., 1984, Regional differences in extracellular ascorbic levels in the rat brain determined by high speed cyclic voltammetry, Brain Res. 299:289–295.PubMedGoogle Scholar
  157. Stephans, S. E., and Yamamoto, B. K., 1994, Methamphetamine-induced neurotoxicity: Roles for glutamate and dopamine efflux, Synapse 17(3):203–209.PubMedGoogle Scholar
  158. Suboticanec, K., Folnegovic-Smalc, V., Turcin, R., Mestrovic, B., and Buzina, R., 1986, Plasma levels and urinary vitamin C excretion in schizophrenic patients, Hum. Nutr. Clin. Nutr. 40C:421–428.PubMedGoogle Scholar
  159. Suboticanec, K., Folnegovic-Smalc, V., Korbar, M., Mestrovic, B., and Buzina, R., 1990, Vitamin C status in chronic schizophrenia. Biol. Psychiat. 28:959–966.PubMedGoogle Scholar
  160. Tarsy, D., 1983, Neuroleptic-induced extrapyramidal reactions: classification, description, and diagnosis, Clin. Neuropharmacolog. 6:S9-S26.Google Scholar
  161. Tauck, D. L., 1992, Redox modulation of NMDA receptor-mediated synaptic activity in the hippocampus Neuroreport 3(9):781–784.PubMedGoogle Scholar
  162. Tolbert, B. M., 1985, Metabolism and function of ascorbic acid and its metabolites. Int. J. Vit. Nutr. Res. 27:121–138.Google Scholar
  163. Tolbert, L. C., Thomas, T. N., Middaugh, L. D., and Zemp, J. W., 1979a, Ascorbate blocks amphetamine-induced turning behavior in rats with unilateral nigro-striatal lesions, Brain Res. Bull. 4:43–48.PubMedGoogle Scholar
  164. Tolbert, L. C., Thomas, T. N., Middaugh, L. D., and Zemp, J. W., 1979b, Effect of ascorbic acid on neurochemical, behavioral, and physiological systems mediated by catecholamines. Life Sci. 25:2189–2195.PubMedGoogle Scholar
  165. Tolbert, L. C., Morris, P. E., Spollen, J. J., and Ashe, S. C., 1992, Stereospecific effects of ascorbic acid and analogues on d1 and d2 agonist binding. Life Sci. 51:921–930.PubMedGoogle Scholar
  166. Torp, R., Danbolt, N. C., Babaie, E., Bjorâs, M., Seeberg, E., Storm-Mathisen, J., Ottersen, O. P., 1994, Differential expression of two glial glutamate transporters in the rat brain: An in situ hybridization study, Eur. J. Neurosci. 6:936–942.PubMedGoogle Scholar
  167. Waddington, J. L., Cross, A. J., Gamble, S. J., and Bourne, R. C., 1983, Dopamine receptor function and spontaneous orofacial dyskinesia in rats during 6-month neuroleptic treatments, in: CNS ReceptorsFrom Molecular Pharmacology to Behavior (P. Mandel and F. W. DeFeudis, eds.), Raven Press, New York, pp. 299–308.Google Scholar
  168. Wagner, G., Lucot, J., Schuster, C., and Seiden, L., 1983, Alpha-methyltyrosine attenuates and reserpine increases methamphetamine-induced neuronal changes, Brain Res. 270:285–288.PubMedGoogle Scholar
  169. Wagner, G C., Jarvis, M. F., and Carelli, R. M., 1985, Ascorbic acid reduces the dopamine depletion induced by MPTP, Neuropharmacology 24:1261–1262.PubMedGoogle Scholar
  170. Wambebe, C., and Sokomba, E., 1986, Some behavioral and EEG effects of ascorbic acid in rats, Psycho-pharmacology 89:167–170.Google Scholar
  171. Wang, Z., and Rebec, G. V., 1993, Neuronal and behavioral correlates of intrastriatal infusions of amphetamine in freely moving rats, Brain Res. 627:79–88.PubMedGoogle Scholar
  172. Waszczak, B. L., and Walters, J. R., 1983, Dopamine modulation of the effects of gammα-aminobutyric acid on substantia nigra pars reticulata neurons, Science 220:218–221.Google Scholar
  173. Weihmuller, F. B., Odell, S. J., and Marshall, J. F, 1992, MK-801 protection against methamphetamine-induced striatal dopamine terminal injury is associated with attenuated dopamine overflow, Synapse 11(2): 155–163.PubMedGoogle Scholar
  174. Weinberger, D. R., Berman, K. F, and Zee, R. F, 1986, Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia. 1: Regional cerebral blood flow evidence, Arch. Gen. Psychiat. 43:114–124.PubMedGoogle Scholar
  175. West, M. O., Michael, A. J., Knowles, S. E., Chapin, J. K., and Woodward, D. J., 1987, Striatal unit activity and the linkage between sensory and motor events, in: Basal Ganglia and Behavior: Sensory Aspects of Motor Functioning (J. S. Schneider, and T. I. Lidsky, eds.), Hans Huber, Toronto, pp. 27–35.Google Scholar
  176. White, L. K., Carpenter, M., Block, N., Basse-Tomusk, A., Gardiner, T. W, Rebec, G. V., 1988, Ascorbate antagonizes the behavioral effects of amphetamine by a central mechanism, Psychopharmacology 94:284–287.PubMedGoogle Scholar
  177. White, L. K., Maurer, M., Kraft, M. E., Oh, C., and Rebec, G. V., 1990, Intrastriatal infusions of ascorbate antagonize the behavioral response to amphetamine, Pharmacol. Biochem. Behav. 36:485–489.PubMedGoogle Scholar
  178. Wilson, R. L., and Wightman, R. M., 1985, Systemic and nigral application of amphetamine both cause an increase in extracellular concentration of ascorbate in the caudate nucleus of the rat, Brain Res. 339:219–226.PubMedGoogle Scholar
  179. Wilson, R. L., Kamata, K., Wightman, R. M., and Rebec, G. V., 1986, Unilateral, intranigral infusions of amphetamine produce differential, bilateral changes in unit activity and extracellular levels of ascorbate in the neostriatum of the rat, Brain Res. 384:342–347.PubMedGoogle Scholar
  180. Wolfarth, S., Coelle, E.-F., Osborne, N. N., and Sontag, K.-H., 1977, Evidence for a neurotoxic effect of ascorbic acid after an intranigral injection in the cat, Neurosci. Lett. 185:183–186.Google Scholar
  181. Yount, S. E., Kraft, M. E., Pierce, R. C., Langley, P. E., and Rebec, G. V., 1991, Acute and long-term amphetamine treatments alter extracellular ascorbate in neostriatum but not nucleus accumbens of freely moving rats, Life, Sci., 49:1237–1244.Google Scholar
  182. Zetterstrom, T., Wheeler, D. B., Boutelle, M. G., and Fillenz, M., 1992, Striatal ascorbate and its relationships to dopamine receptor stimulation and motor activity, Eur. J. Neurosci. 3:940–946.Google Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • George V. Rebec
    • 1
  1. 1.Program in Neural Science, Department of PsychologyIndiana UniversityBloomingtonUSA

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