Elsevier

Brain Research Bulletin

Volume 21, Issue 2, August 1988, Pages 257-263
Brain Research Bulletin

Time course of MPTP-induced degeneration of the nigrostriatal dopamine system in C57 BL/6 mice

https://doi.org/10.1016/0361-9230(88)90240-7Get rights and content

Abstract

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a parkinsonism-inducing dopamine (DA) neurotoxin most effective in primates MPTP also causes a degeneration of both perikarya and axon terminals of the nigrostriatal DA neurons in C57 BL/6 mice. The time courses of the changes in tyrosine hydroxylase immunoreactive objects, endogeneous DA concentrations and specifically bound 3H-mazindol as markers of the integrity of DA neurons were studied in substantia nigra and striatum of adult C57 BL/6 mice, after systemic treatment with MPTP or intranigral injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). A rapid decrease in the three parameters studied was found in the substantia nigra during the first 2 days after MPTP-treatment while the MPTP-induced effects in the striatum were more protracted and maximal reduction was observed 7 days after MPTP. A basically similar pattern was found when studying the 6-OHDA-induced anterograde degeneration of the nigrostriatal system. These results indicate that in C57 BL/6 mice, MPTP primarily destroys the DAergic perikarya with a subsequent anterograde degeneration of the striatal axon terminals, although a limited rapid destruction of some striatal terminals cannot be excluded.

References (26)

  • C.J. Schmidt et al.

    In vitro release of tritiated monoamines from rat CNS tissue by the neurotoxic compound 1-methyl-phenyl-tetrahydropyridine

    Eur. J. Pharmacol.

    (1984)
  • N.-E. Andén et al.

    Early and selective increase in brain dopamine levels after axotomy

    Experientia

    (1972)
  • R.S. Burns et al.

    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

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