Evidence for a dissociation between MPTP toxicity and tyrosinase activity based on congenic mouse strain susceptibility

The neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( MPTP) is one of the most valuable available models for investigating critic al aspects of human Parkinson's disease. In order to analyze the relevance of pigmentation for MPTP sensitivity, we compared C57Bl/6 wild-type mice wi th the albino mutant C57Bl/6J-Tyr(c-2J) of the same strain. These animals w ere treated either with systemic MPTP or with saline and were examined in b ehavioral tests. Seven days after treatment, the contents of dopamine and o ther monoamines were determined postmortem in the neostriatum and ventral s triatum. Furthermore, the numbers of tyrosine hydroxylase-positive cells we re counted in the substantia nigra and ventral tegmental area. Open field t esting showed that rearing activity was drastically reduced as an acute eff ect of MPTP in both wild type and mutants; however, subsequent recovery to control levels was faster in wild-type mice. Nest building also indicated s train-dependent effects, since it was delayed only in mutants treated with MPTP. Neurochemically, MPTP led to severe neostriatal dopamine depletions, which did not differ significantly between wild-type (72.9%) and mutant mic e (82.1%). Less severe dopamine depletions were also found in the ventral s triatum. Histologically, a loss of tyrosine hydroxylase-labeled cells was o bserved only in the substantia nigra of both wild-type and mutant mice (13. 3 and 21.3%, respectively), but not in the ventral tegmental area. Together , our data do not provide evidence that tyrosinase-deficient mice are less affected by MPTP treatment than the comparable wild type, thus arguing stro ngly against the hypothesis that enhanced MPTP sensitivity in pigmented mou se strains is caused by tyrosinase activity. (C) 2001 Academic Press.