Proposed research will investigate the mechanisms underlying behavior/motor deficits consequent to MPTP-induced loss of substantia nigra (SN) dopaminergic neurons and extensive striatal DA depletion and examine the bases for functional recovery following a large DA-depleting lesion. We have previously suggested that volume transmission of DA may play a critical role in functional recovery following a large DA-depleting lesion, and that the regulation of the DA transporter may play a critical role in influencing the ability of DA to diffuse away from its site of release. In the present application, we will use a combination of quantitative and functional techniques (in situ hybridization histochemistry, immunohistochemistry, ligand binding, and in vivo electrochemistry) to study the DA transporter and the presynaptic DA system. We will assess the degree to which functional recovery in MPTP-treated cats is accompanied by regional recovery of and release of DA from residual DA terminals and the degree to which such changes may be accompanied by decreased DA transporter number and/or function. We will also examine potential differences in the above-mentioned measures between animals and spontaneous recovery versus stimulated recovery (with GM1 ganglioside) from parkinsonism. Preliminary data suggests that spontaneous recovery may represent more a true compensatory of adaptive process whereas stimulated recovery may reflect a reactivation of a developmental program and a rebuilding of the natural pattern of DA innervation. Other studies will use quantitative receptor autoradiography, in situ hybridization histochemistry, and in vivo microdialysis to: A) examine postsynaptic dopaminergic mechanisms relating to parkinsonism and functional recovery from parkinsonism and B) examine the contributions of non-dopaminergic systems (GABA, enkephalin, excitatory amino acids) to MPTP-induced parkinsonism and assess the extent to which compensatory changes in these systems may contribute to functional recovery from parkinsonism. Behavioral electrophysiological studies will examine the properties of striatal and motor thalamic neurons in normal, symptomatic, and spontaneous and GM1-recovered MPTP-treated cats performing a learned sensorimotor task. These studies will examine the relationships between restoration of sensorimotor function and the integrity of the pre-synaptic DA system. Parkinson's disease represents a disorder in which compensatory processes have failed. The continued study of MPTP-treated cats is important because they do recover from parkinsonism, and therefore display properties of a successfully compensated system. The proposed research will provide a fuller understanding of the processes underlying functional recovery from extensive DA cell loss.
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