Administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a neurotoxin highly selective for midbrain dopamine neurons, to nonhuman primates produces a pattern of dopamine neuron loss and movement disorders similar to that seen in Parkinson's disease. In both idiopathic parkinsonism and MPTP-induced parkinsonism, the functional state of residual midbrain dopamine neurons is unclear. This proposal focuses on characterizing the structural and functional properties of residual dopamine neurons before and after exposure to glial cell line-derived neurotrophic factor (GDNF), a potent dopaminergic trophic factor which induces functional recovery in parkinsonian monkeys. In this project, the PI will specifically aim to test the following hypotheses: 1) That GDNF exerts neurorestorative effects on MPTP-injured dopamine neurons in the adult brain. Changes in the characteristics of surviving substantia nigra dopamine neurons following GDNF treatment will be analyzed using an optical dissector/stereological cell counting approach to determine cell number and quantitative image analysis to measure cell size. 2) That improvements in parkinsonian features following GDNF administration correlate closely with the upregulation of dopamine markers such as tyrosine hydroxylase and the dopamine transporter in midbrain dopamine neurons. 3) That intracerebral administration of GDNF significantly alters nigrostriatal dopamine metabolism. Basal levels of dopamine and its metabolites, characteristics of potassium-evoked dopamine release and high affinity dopamine uptake will be analyzed in the putamen and substantia nigra of GDNF-treated and vehicle-treated parkinsonian rhesus monkeys using iv vivo microdialysis techniques. These studies should increase the understanding of the properties of residual midbrain dopamine neurons in nonhuman primates with MPTP-induced parkinsonism.
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