Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter.

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.

journal_name

J Neurochem

authors

Gainetdinov RR,Fumagalli F,Jones SR,Caron MG

doi

10.1046/j.1471-4159.1997.69031322.x

subject

Has Abstract

pub_date

1997-09-01 00:00:00

pages

1322-5

issue

3

eissn

0022-3042

issn

1471-4159

journal_volume

69

pub_type

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