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Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter
R R Gainetdinov1, F Fumagalli, S R Jones
1Howard Hughes Medical Institute Laboratories, Department of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina 27710, U.S.A.
Abstract:
The neurotoxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was tested on mice lacking the dopamine (DA) transporter (DAT-/- mice). Striatal tissue DA content and glial fibrillary acidic protein (GFAP) mRNA expression were assessed as markers of MPTP neurotoxicity. MPTP (30 mg/kg, s.c., b.i.d.) produced an 87% decrease in tissue DA levels and a 29-fold increase in the level of GFAP mRNA in the striatum of wild-type animals 48 h after administration. Conversely, there were no significant changes in either parameter in DAT-/- mice. Heterozygotes demonstrated partial sensitivity to MPTP administration as shown by an intermediate value (48%) of tissue DA loss. Direct intrastriatal infusion of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+; 10 mM), via a microdialysis probe produced a massive efflux of DA in wild-type mice (>320-fold). In the DAT-/- mice the same treatment produced a much smaller increase in extracellular DA (sixfold), which is likely secondary to tissue damage due to the implantation of the dialysis probe. These observations show that the DAT is a mandatory component for expression of MPTP toxicity in vivo.
Insights
The dopamine transporter (DAT) is essential for the neurotoxic effects of MPTP. Mice lacking DAT show no MPTP-induced dopamine depletion or GFAP increase, confirming DAT
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that selectively damages dopaminergic neurons.
- The dopamine transporter (DAT) plays a crucial role in regulating dopamine homeostasis and is implicated in MPTP neurotoxicity.
Purpose of the Study:
- To investigate the role of the dopamine transporter (DAT) in MPTP-induced neurotoxicity.
- To determine if DAT is a mandatory component for MPTP's toxic effects in vivo.
Main Methods:
- MPTP neurotoxicity was assessed in mice lacking the dopamine transporter (DAT-/-) and wild-type littermates.
- Striatal dopamine content and glial fibrillary acidic protein (GFAP) mRNA expression were measured as indicators of neurotoxicity.
- Direct intrastriatal infusion of MPP+ was performed using microdialysis.
Main Results:
- MPTP administration caused significant dopamine depletion and GFAP mRNA increase in wild-type mice but not in DAT-/- mice.
- DAT heterozygotes exhibited partial sensitivity to MPTP.
- Intrastriatal MPP+ infusion caused a massive dopamine efflux in wild-type mice, but a much smaller increase in DAT-/- mice.
Conclusions:
- The dopamine transporter (DAT) is essential for the in vivo neurotoxicity of MPTP.
- DAT-/- mice are resistant to MPTP-induced dopaminergic neurodegeneration.
- These findings highlight the critical role of DAT in mediating the toxic effects of MPTP.