Abstract
The number of nigral dopamine neurons and striatal dopamine levels are reduced by 70% in the adult weaver mutant mouse (wv/wv), whereas these parameters are essentially unchanged in the heterozygote (wv/+). We hypothesized that the remaining nigral dopamine neurons and/or striatal dopamine levels in the weaver would be less sensitive to neurotoxic or dopamine-depleting agents and that nigral neurons in the heterozygote would be more vulnerable. Mice were treated with the dopaminergic neurotoxin MPTP using different injection schedules and also with reserpine. There was a similar percent decrease in striatal DA in weavers and heterozygotes compared to normal mice after these treatments. We did observe a gene-dose-related lethality to the highest dose treatment with MPTP. These results suggest that the remaining dopaminergic neurons in the weaver are not different from those in normal mice in their capacity to respond to MPTP and reserpine.
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Abbreviations
- DA:
-
3,4-dihydroxyphenylethylamine, dopamine
- DHBA:
-
dihydroxybenzylamine
- MPTP:
-
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- TH:
-
tyrosine hydroxylase
- MAO:
-
monoamine oxidase
References
Chiba K., Trevor A. J., and Castagnoli N., Jr. (1985) Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes.Biochem. Biophys. Res. Commun. 128, 1228–1232.
Donnan G. A., Kaczmarczyk S. J., McKenzie J. S., Rowe P. J., Kalnins R. M., Mendelsohn F. A. O. (1987) Regional and temporal effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on dopamine uptake sites in mouse brain.J. Neurological Sci. 81, 261–271.
Fuller R. W. and Hemrick-Luecke S. K. (1985) Effects of amfonelic acid, α-methyltyrosine, Ro 4-1284 and haloperidol pretreatment on the depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.Res. Commun. Chem. Pathol. Pharmacol. 48, 17–25.
Fuller R. W., Hemrick-Luecke S. K., and Perry K. W. (1988) Deprenyl antagonizes acute lethality of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.J. Pharmacol. Exp. Therap. 247, 531–535.
German D. C., Manaye K. F., Sonsalla P. K., and Brooks B. A. (1992) Midbrain dopaminergic cell loss in Parkinson’s disease and MPTP-induced parkinsonism: sparing of calbindin-D28k-containing cells.Ann. NY Acad. Sci. 648, 42–62.
Giachetti A. and Shore P. A. (1978) Minireview. The reserpine receptor.Life Sci. 23, 89–92.
Giovanni A., Sieber B.-A., Heikkila R. E., and Sonsalla P. K. (1991) Correlation between the neostriatal content of the 1-methyl-4-phenylpyridinium species and dopaminergic neurotoxicity following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration to several strains of mice.J. Pharmacol. Exp. Therap. 257, 691–696.
Gupta M., Felten D. L., and Gash D. M. (1984) MPTP alters central catecholamine neurons in addition to the nigrostriatal system.Brain Res. Bull. 13, 737–742.
Gupta M., Gupta B. K., Thomas R., Bruemmer V., Sladek J. R., Jr., and Felten D. L. (1986) Aged mice are more sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment than young adults.Neurosci. Lett. 70, 326–331.
Heikkila R. E., Hess A., and Duvoisin R. C. (1984) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice.Science 224, 1451–1453.
Javitch J. A., D’Amato R. J., Strittmatter S. M., and Snyder S. H. (1985) Parkinsonism-inducing 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. USA 82, 2173–2177.
Kostrzewa R. M. and Jacobowitz D. M. (1974) Pharmacological actions of 6-hydroxydopamine.Pharmacol. Rev. 26, 199–288.
Langston J. W., Forno L. S., Rebert C. S., and Irwin I. (1984) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in the squirrel monkey.Brain Res. 292, 390–394.
Lowry O. H., Rosebrough N. J., Farr A. L., and Randall R. J. (1951) Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193, 265–275.
Markey S. P., Johannessen J. N., Chiueh C. C., Burns R. S., and Herkenham M. A. (1984) Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism.Nature 311, 464–467.
Mayer R. A., Jarvis M. F., and Wagner G. C. (1985) Cocaine blocks the dopamine depletion induced by MPTP.Res. Commun. Chem. Pathol. Pharmacol. 49, 145–148.
Mayer R. A., Kindt M. V., and Heikkila R. E. (1986) Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport.J. Neurochem. 47, 1073–1079.
Melamed E., Rosenthal J., Cohen O., Globus M., and Uzzan A. (1985) Dopamine but not norepinephrine or serotonin uptake inhibitors protect mice against neurotoxicity of MPTP.Eur. J. Pharmacol. 116, 179–181.
Rakic P. and Sidman R. L. (1973) Sequence of developmental abnormalities leading to granule cell deficit in cerebellar cortex of weaver mutant mice.J. Comp. Neurol. 152, 103–132.
Ricaurte G. A., Langston J. W., DeLanney L. E., Irwin I., and Brooks J. D. (1985) 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.
Richter J. A., Stotz E. H., Ghetti B., and Simon J. R. (1992) Comparison of alterations in tyrosine hydroxylase, dopamine levels, and dopamine uptake in the striatum of the weaver mutant mouse.Neurochem. Res. 17, 437–441.
Schneider J. S. (1992) Effects of age on GM1 ganglioside-induced recovery of concentrations of dopamine in the striatum in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice.Neuropharmacology 31, 185–192.
Shore P. A. (1972) Transport and storage of biogenic amines.Annu. Rev. Pharmacol. Toxicol. 12, 209–226.
Sidman R. L., Green M. C., and Appel S. H., (1965)Catalog of the Neurological Mutants of the Mouse. Harvard University Press, Cambridge, MA.
Simon J. R., Yu H., Richter J. A., Vasko M. J., and Ghetti B. (1991) In vitro release of endogenous dopamine from the striatum of the weaver mutant mouse.J. Neurochem. 57, 1478–1482.
Singer T. P., Castagnoli N., Jr., Ramsay R. R., and Trevor A. J. (1987) Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.J. Neurochem. 49, 1–8.
Sonsalla P. K. and Heikkila R. E. (1986) The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice.Eur. J. Pharmacol. 129, 339–345.
Stotz E. H., Simon J. R., Ghetti B., and Richter J. A. (1989) Effect of MPTP on striatal dopamine levels in the weaver mutant mouse.Soc. Neurosci. Abs. 15, 97.
Sundstrom E., Stromberg I., Tsutsumi T., Olson L., and Jonsson G. (1987) Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57 BL/6 mice. Comparison with three other strains.Brain Res. 405, 26–38.
Triarhou L. C. and Ghetti B. (1989) The dendritic dopamine projection of the substantia nigra: phenotypic denominator of weaver gene action in hetero-and homozygosity.Brain Res. 501, 373–381.
Triarhou L. C., Norton J., and Ghetti B. (1988) Mesencephalic dopamine cell deficit involves areas A8, A9 and A10 in weaver mutant mice.Exp. Brain Res. 70, 256–265.
Ungerstedt U. (1971) Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal system.Acta Physiol. Scand. Suppl. 367, 95–122.
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Richter, J.A., Ghetti, B. & Simon, J.R. Dopamine-depleting effects of MPTP and reserpine in weaver mutant mice. Molecular and Chemical Neuropathology 20, 219–228 (1993). https://doi.org/10.1007/BF03160075
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DOI: https://doi.org/10.1007/BF03160075