The goal of the proposed work is to better understand neuronal compensation in Parkinson's disease. Symptoms of this neurodegenerative disorder are associated with the loss of nigrostriatal dopamine neurons but do not present until deficits are severe. It is postulated that potent adaptive changes in dopamine neurotransmission maintain function during the preclinical or presymptomatic phase. These adaptive mechanisms will be examined in a widely used animal model of Parkinson's disease, the rat with 6-hydroxydopamine lesions. The proposed experiments will study the regulation of extracellular dopamine in the partially denervated striatum, a condition that mimics the preclinical phase. Previous studies using the technique of microdialysis have documented normal concentrations of extracellular dopamine in the lesioned striatum despite losses of up to 80 % of the dopamine terminals. The proposed work will extend these observations by directly investigating the mechanisms responsible for maintaining extracellular dopamine levels. To accomplish this aim, real-time microsensors will be employed to monitor dynamic changes in extracellular dopamine elicited by transient electrical stimulation. In situ rate constants for dopamine release and uptake will be determined from the chemical measurements. Release and uptake are fundamental to dopamine neurotransmission and are the primary determinants of extracellular dopamine concentrations in the brain. A novel hypothesis will be tested. The hypothesis states that normal concentrations of extracellular dopamine are generated in the partially denervated striatum without active compensatory changes in dopamine release and uptake. An understanding of the adaptive changes that maintain dopamine function during the preclinical phase of Parkinson's disease could advance diagnosis and treatment of this disorder as well as provide new insight into other neurodegenerative disease, brain function during the normal aging process and neuronal plasticity.
