Abstract
We have earlier demonstrated that 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) produces a direct toxicity on DA neurons in the substantia nigra (SN) and norepinephrine (NE) neurons in the locus coeruleus (LC) other than in the terminals. These results suggest that DA neurons in the SN and NE neurons in the LC are possibly able to uptake MPP+ through the DA and NE uptake systems, respectively, presumably via DA and NE dendrites. The present study examined this hypothesis. Adult male BALB/c mice were used. In the first part, animals received various combinations of nomifensine (NOM, a specific DA uptake blocker) and MPTP treatment. NOM was infused to the SN or striatum at 1.5 μg and 3.0 μg per day for a total of seven days. The infusion volume was 0.25 and 0.5 μl, respectively. MPTP was given systemically (IP) at 30 mg/kg per day for a total of seven days. On each day, NOM was given 30 min prior to MPTP injection. In the second part, animals received the same combinations of desimipramine (DMI, a specific NE uptake blocker) and MPTP treatments. DMI was infused to the LC and hippocampus at 1.25 μg and 2.5 μg per day 30 min before MPTP injection for a total of 7 days. The volumes of infusion were 0.25 μl in the LC and 0.5 μl in the hippocampus. Animals were subject to locomotor activity test 7 days after the last MPTP, MPP+ (saline) injections. They were then sacrificed and brain tissues of the striatum and hippocampus were subject to DA and NE analyses with HPLC fluorescence detection. Results indicated that MPTP consistently and markedly decreased DA level in the striatum and NE level in the hippocampus. It also impaired locomotor activity and produced long-lasting tremor in mice. NOM pretreatment in the striatum completely prevented MPTP’s toxicity, while NOM pretreatment in the SN only partially, but significantly, prevented MPTP’s toxicity on both DA and motor activity.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Arai, N., Misugi, K., Goshima, Y. and Misu, Y.: Evaluation of a l-methyl-4-phenyl-1, 2, 3, 6-tetra-hydropyridine (MPTP)-treated C57 black mouse model for parkinsonism. Brain Res. 515: 57–63, 1990.
Burns, R. S., Chiueh, C. C., Markey, S. P., Ebert, M. H., Jacobwitz, D. M. and Kopin, I. J.: A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Proc. Natl. Acad. Sci. U. S. A. 80: 4546–4550, 1983.
Campbell, K. J., Takada, M. and Hattori, T.: Evidence for retrograde axonal transport of MPP+ in the rat. Neurosci. Lett. 118: 151–154, 1990.
Chang, F. W., Wang, S. D., Lu, K. T. and Lee, E. H. Y.: Differential interactive effects of gliotoxin and MPTP in the substantia nigra and the locus coeruleus in BALB/c mice. Brain Res. Bull. 31: 253–266, 1993.
Chiba, K., Trevor, A. J. and Castagnoli, N., Jr.: Activie uptake of MPP+, a metabolite of MPTP, by brain synaptosomes. Biochem. Biophys. Res. Commun. 128: 1228–1232, 1985.
Chiueh, C. C., Johannessen, J. N., Chesselet, M. F. and Markey, S. P.: Neurotoxic mechanism of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and its oxidative metabolites in the nigrostriatal system of C57BL6 mice. Fed. Proc. 44: 893, 1985.
Colotla, V. A., Flores, E., Oscos, A., Meneses, A. and Tapia, R.: Effects of MPTP on locomotor activity in mice. Neurotoxicol. Teratol. 12: 405–407, 1990.
Forno, L. S., Langston, J. W., Delanney, L. E., Irwin, I. and Ricaurte, G. A.: Locus ceruleus lesions and eosinophilicinclusions in MPTP-treated mondeys. Ann. Neurol. 20: 449–455, 1986.
Gerlach, M., Riederer, P., Przuntek, H. and Youdim, B. H.: MPTP mechanisms of neurotoxic-ity and their implications for parkinson’s disease. Eur. J. Pharmacol.208: 273–286, 1991.
Gray, E.G. and Whittaker, V. P.: The isolation of nerve endings from brain: an electron microscopic study of cell fragments divided by homogenization and centrifugation. J. Anat.96: 79–88, 1962.
Groves, P. M.. Wilson, C. J., Young, S. J. and Rebec, G. V.: Self-inhibition by dopaminergic neurons. Science, 190: 522–529, 1975.
Gupta, M., Felten, D. L. and Gash, D. M.: MPTP alters central catecholamine neurons in addition to the nigrostriatal system. Brain Res. Bull. 13: 737–742, 1984.
Hallman, H., Lange, J., Olson, L., Stromberg, I. and Jonsson, G.: Neurochemical and histochemical characterization of neurotoxic effects of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine on brain catecholamine neurons in the mouse. J. Neurochem. 44: 117–127, 1985.
Heikkila, R. E., Hess, A. and Duvoisin. R. C.: Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine in mice. Science (Wash. DC) 224: 1451–1453, 1984a.
Heikkila, R. E., Manzino, L., Cabbat, F. S. and Duvoisin, R. C.: Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine by monoamine oxidase inhibitors. Nature (Lond.) 311: 467–469, 1984b.
Hu, S. C., Chang, F. W., Sung, Y. J., Hsu, W. M. and Lee, E. H. Y.: Neurotoxic effects of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine in the substantia nigra and the locus coeruleus in BALB/c mice. J. Pharmacol. Exp. Ther. 259: 1379–1387, 1991.
Jarvis, M. F.and Wagner, G. C.: 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced neurotoxicity in the rat; characterization and age-dependent effects. SYNAPSE, 5: 104–112, 1990.
Javitch. J. A., D’Amato, R. J., Strittmatter, S. M. and Snyder, S. H.: Parkinsonism-induc-ing neurotoxin, N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine: Uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc. Natl. Acad. Sci. U. S.A. 82: 2173–2177, 1985.
Jenner, P., Rupniak, N. M. J., Rose, S., Kelly, E., Kilpatrick, G., Less, A. and Marsden, C. D.: 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced parkinsonism in the common marmoset. Neurosci. Lett. 50: 85–90, 1984.
Kuriyama, T., Taguchi, J. I. and Kuriyama, K.: Functional alterations in striatal cholinergic and striatonigral gabaergic neurons following 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) administration. Neurochem. Int. 16: 319–329, 1990.
Langston, J. W., Forno, L. S., Rebert, C. S. and Irwin, I. 1-methyl-1, 2, 5, 6-tetrahydropyridine causes selective damage to the zona compacta of the substantia nigra in the squirrel monkey. Brain Res. 292: 390–394, 1984.
Lee, E. H. Y., Lin, Y. P. and Yin, T. H.: Effects of lateral and medial septal lesions on various activity and reactivity measures in rats. Physiol. Behave. 42: 97–102, 1987.
Lehmann, A.: Atlas stereotaxique du cerveau de la souris. 1974.
Lowry, O. H., Rosebrough, N. J., Farr, A. L. and Randall, R. J.: Protein measurement with the folin phenol reagent. J. Biol. Chem. 193: 265–275, 1951.
Mann, D. M. A. and Yates, P. O.: Pathological basis for neurotransmitter changes in Parkinson’s disease. Neuropathol. Appl. Neurobiol. 9: 3–19, 1983.
Mann, D. M. A. Yates, P. O. and Hawkes, J.: The pathology of thehuman locus ceruleus. Clin. Neuropathol. 2: 1–7, 1983.
Matsuda, L. A., Schmidt, C. J., Hanson, G. R. and Gibb, J. W.: Effect of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) on striatal tyrosine hydroxylase and tryptophan hydroxylase in rat. Neuropharmacology, 25: 249–255, 1986.
Mitchell, I. J., Cross, A. J., Sambrook, M. A. and Crossman, A. R.: Sites of the neurotoxic action of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine in the macaque monkey include the ventral tegmental area and the locus coeruleus. Neurosci. Lett. 61: 195–200, 1985.
Nissbrandt, H., Sundstrom, E., Jonsson, G., Hjorth, S. and Carlsson, A.: Synthesis and release of dopamine in rat brain: comparison between substantia nigra pars compacta, pars reticulata, and striatum. J. Neurochem. 52: 1170–1182, 1989.
Peat, M. A. and Gibb, J. W.: High performance liquid Chromatographic determination of indoleamines, dopamine and norepinephrine in rat brain with fluorimetric detection. Anal. Biochem. 128: 275–280, 1983.
Ransom, B. R., Kunis, D. M., Irwin, I. and Langston, J. W.: Astrocytes convert the parkinsonism inducing neurotoxin, MPTP, to its active metabolite, MPP+. Neurosci. Lett. 75: 323–328, 1987.
Reid, W. G. J., Broe, G. A., Hely, M. A., Morris, J. G. L., Williamson, P. M., O’Sullivan, D. J., Rail, D., Genge, S. and Moss, N. G.: The neuropsychology of de novo patients with age on onset. Int. J. Neurosci. 48: 205–217, 1989.
Ricaurte, G. A., Langston, J. W., Delanney, L. E., Irwin, I. and Brooks, J. D.: Dopamine uptake blockers protect against the dopamine depleting effect of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) in the mouse striatum. Neurosci. Lett. 59: 259–264, 1985.
Robertson, G. S., Damsma, G. and Fibiger, H. C.: Characterization of dopamine release in the substantia nigra by in vivo microdialysis in freely moving rats. J. Neurosci. 11: 2209–2216, 1991.
Segal, D. S. and Kuczenski, R.: Tyrosine hydroxylase activity: Regional and subcellular distribution in brain. Brain Res. 68: 261–266, 1974.
Siegel, M.: Nonparametric Statistics for the Behavioral Science, McGraw-Hill Company, New York, 1965.
Singer, T. P. and Ramsay, R. R.: Mechanism of the neurotoxicityof MPTP. FEBS Lett. 274: 1-8, 1990.
Sundstrom, E., Fredriksson, A. and Archer, T.: Chronic neurochemical and behavioral changes in MPTP-lesioned C57BL/6 mice: A model for Parkinson’s disease. Brain Res. 528: 181–188, 1990.
Svensson, T. H., Bunney, B. S. and Aghajanian, G. K.: Inhibition of both noradrenergic and serotonergic neurons in brain by the a-adrenergic agonist clonidine. Brain Res. 92: 291–306, 1975.
Takada, M., Li, Z. K. and Hattori, T.: Intracerebral MPTP injections in the rat cause cell loss in the substantia nigra, ventral tegmental area and dorsal raphe. Neurosci. Lett. 78: 145–150, 1987.
Tetrud J. W. and Langston, J. W.: Tremor in MPTP-induced parkinsonism. Neurology,42: 407–410, 1992.
Van Dognen, V. P. A. M.: The human locus coeruleus in neurology and psychiatry (Parkinson’s, Lewy body, Hallervorden-Spatz, Alzheimer’s and Korsakoff s disease, (pre) senile dementia, schizophrenia, affective disorders, psychosis). Prog. Neurobiol. 17: 97–139, 1981.
Willoughby, J., Cowburn, R. F., Hardy, J. A., Glover, V. and Sandler, M.: 1-Methyl-4-phenylpyridine uptake by human and rat striatal synaptosomes. J. Neurochem. 52: 627–631, 198
Wilson, J. A., Doyle, T. J. and Lau, Y. S.: MPTP, MPDP+ and MPP+ cause decreases in dopamine content in mouse brain slices. Neurosci. Lett. 108: 213–218, 1990.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1995 Springer Science+Business Media New York
About this chapter
Cite this chapter
Lee, E.H.Y., Lu, K.T. (1995). Neurotoxicity of MPTP and Uptake of MPPT into Dopamine and Norepinephrine Neurons in Mice. In: Tang, L.C., Tang, S.J. (eds) Neurochemistry in Clinical Application. Advances in Experimental Medicine and Biology, vol 363. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1857-0_6
Download citation
DOI: https://doi.org/10.1007/978-1-4615-1857-0_6
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-5754-4
Online ISBN: 978-1-4615-1857-0
eBook Packages: Springer Book Archive