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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Academic Research Enhancement Awards (AREA) (R15)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (02))
Program Officer
Sheehy, Paul A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
East Tennessee State University
Schools of Medicine
Johnson City
United States
Zip Code
Nowak, Przemyslaw; Bortel, Aleksandra; Dabrowska, Joanna et al. (2007) Amphetamine and mCPP effects on dopamine and serotonin striatal in vivo microdialysates in an animal model of hyperactivity. Neurotox Res 11:131-44
Kostrzewa, R M; Kostrzewa, J P; Brus, R et al. (2006) Proposed animal model of severe Parkinson's disease: neonatal 6-hydroxydopamine lesion of dopaminergic innervation of striatum. J Neural Transm Suppl :277-9
Kostrzewa, R M; Nowak, P; Kostrzewa, J P et al. (2005) Peculiarities of L: -DOPA treatment of Parkinson's disease. Amino Acids 28:157-64
Kostrzewa, Richard M; Kostrzewa, John P; Nowak, Przemyslaw et al. (2004) Dopamine D2 agonist priming in intact and dopamine-lesioned rats. Neurotox Res 6:457-62
Segura Aguilar, Juan; Kostrzewa, Richard M (2004) Neurotoxins and neurotoxic species implicated in neurodegeneration. Neurotox Res 6:615-30
Brown, Russell W; Thompson, Kenyatta D; Thompson, Kimberly N et al. (2004) Adulthood nicotine treatment alleviates behavioural impairments in rats neonatally treated with quinpirole: possible roles of acetylcholine function and neurotrophic factor expression. Eur J Neurosci 19:1634-42
Brus, Ryszard; Nowak, Przemyslaw; Szkilnik, Ryszard et al. (2004) Serotoninergics attenuate hyperlocomotor activity in rats. Potential new therapeutic strategy for hyperactivity. Neurotox Res 6:317-25
Brus, Ryszard; Kostrzewa, Richard M; Nowak, Przemyslaw et al. (2003) Ontogenetic quinpirole treatments fail to prime for D2 agonist-enhancement of locomotor activity in 6-hydroxydopamine-lesioned rats. Neurotox Res 5:329-38
Kostrzewa, Richard M; Segura-Aguilar, Juan (2003) Novel mechanisms and approaches in the study of neurodegeneration and neuroprotection. a review. Neurotox Res 5:375-83
Brown, Russell W; Gass, Justin T; Kostrzewa, Richard M (2002) Ontogenetic quinpirole treatments produce spatial memory deficits and enhance skilled reaching in adult rats. Pharmacol Biochem Behav 72:591-600

Showing the most recent 10 out of 16 publications