Dopamine (DA) is the catecholamine most easily auto-oxidized to reactive o-quinones and is most involved in generation of other reactive oxygen species (ROS), of which hydroxyl radical (OH) is the most reactive. It is for this reason that DA is suspect as an autotoxin, over time, destroys DA nerves, including substantia nigra pars compacta, resulting in Parkinson's disease. Counter to this view of DA as an autotoxin, they found that basal OH in neostriatum was low when DA innervation of neostriatum was intact, but that OH increased several fold if DA innervation suppresses OH generation in the neostriatum. Various degrees of DA-denervation of neostriatum (15-99%) first will be produced by giving 6-hydroxydopamine to neonatal rats. In adulthood an in vivo microdialysis probe will be implanted, with the probe tip residing in neostriatum; and salicylate will be included in microdialysates as a spin trap for OH, detected with HPLC/EC as 2,5-dihydroxybenzoic acid and 2,3-DHBA. To eliminate other ontogenetic processes as factors associated with increased OH formation in DA-denervated rats, the neostriatum of one group of rats will be unilaterally denervated at 8-10 wk by 7-OHDA injected into Snpc. To test that DA per se is involved, a group of rats will be DA depleted with a-methyl-p-tyrosine. Other experiments to test the role of DA primarily as an anti-oxidant include 1) effect of subchronic L-DOPA treatment on OH; 2) direct inhibition of OH formation by DA microdialysates; 3) mediation of OH generation by glutamic acid in DA-denervated neostriatum. Microdialysates (extraneuronal compartment) and whole striatum (mainly intraneuronal compartment) will be analyzed in all studies, to assess DA effects in each compartment and verify completeness of DA-denervation. Findings should validate or refute the hypothesis that DA innervation is primarily neuroprotectant and suppressive of OH in neostriatum.
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