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The Journal of Neuroscience, October 12, 2005, 25(41):9428-9433; doi:10.1523/JNEUROSCI.0130-05.2005

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BRIEF COMMUNICATION
Dopamine Depletion Does Not Protect against Acute 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Toxicity In Vivo

Daphne M. Hasbani,¹ Francisco A. Perez,² Richard D. Palmiter,² and Karen L. O'Malley¹

¹Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, and ²Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195

Dopamine (DA) has been postulated to play a role in the loss of dopaminergic substantia nigra (SN) neurons in Parkinson's disease because of its propensity to oxidize and form quinones and other reactive oxygen species that can alter cellular function. Moreover, DA depletion can attenuate dopaminergic cell loss in vitro. To test the contribution of DA to SN impairment in vivo, we used DA-deficient mice, which lack the enzyme tyrosine hydroxylase in dopaminergic cells, and mice pharmacologically depleted of DA by -methyl-p-tyrosine pretreatment. Mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that produces parkinsonian pathology in humans, nonhuman primates, and rodents. In contrast to in vitro results, genetic or pharmacologic DA depletion did not attenuate loss of dopaminergic neurons in the SN or dopaminergic neuron terminals in the striatum. These results suggest that DA does not contribute to acute MPTP toxicity in vivo.

Key words: Parkinson's disease; MPTP; dopamine; neurodegeneration; substantia nigra; animal models

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Received Jan 11, 2005; revised August 26, 2005; accepted September 2, 2005.

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