Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter

Exp Neurol. 1999 Feb;155(2):268-73. doi: 10.1006/exnr.1998.6995.


MPTP has been shown to induce parkinsonism both in human and in nonhuman primates. The precise mechanism of dopaminergic cell death induced following MPTP treatment is still subject to intense debate. MPP+, which is the oxidation product of MPTP, is actively transported into presynaptic dopaminergic nerve terminals through the plasma membrane dopamine transporter (DAT). In this study, we used mice lacking the DAT by homologous recombination and demonstrated that the MPTP-induced dopaminergic cell loss is dependent on the presence of the DAT. For this we have used tyrosine hydroxylase immunoreactivity (TH-IR) labeling of dopamine cells of the substantia nigra compacta in wild-type, heterozygote, and homozygote mice that were given either saline or MPTP treatments (two ip injections of 30 mg/kg, 10 h apart). Our results show a significant loss of TH-IR in wild type (34.4%), less loss in heterozygotes (22.5%), and no loss in homozygote animals. Thus dopamine cell loss is related to levels of the DAT. These results shed light on the degenerative process of dopamine neurons and suggest that individual differences in developing Parkinson's disease in human may be related to differences of uptake through the DAT of a yet unidentified neurotoxin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Death / drug effects
  • Dopamine / metabolism*
  • Dopamine Agents / toxicity*
  • Dopamine Plasma Membrane Transport Proteins
  • Genotype
  • Humans
  • Immunohistochemistry
  • MPTP Poisoning*
  • Male
  • Membrane Glycoproteins*
  • Membrane Transport Proteins*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Neurons / drug effects*
  • Tyrosine 3-Monooxygenase / metabolism


  • Carrier Proteins
  • Dopamine Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • SLC6A3 protein, human
  • Slc6a3 protein, mouse
  • Tyrosine 3-Monooxygenase
  • Dopamine