The most widely held model of the pathophysiology of Parkinson's disease postulates that striatal dopamine loss in parkinsonism results increased striatal inhibition of the external pallidal segment (GPe), which leads to disinhibition of the subthalamic nucleus (STN) and internal pallidal segment (GPi). Increased STN and GPi activity is known to be crucial for parkinsonian signs. This model has greatly facilitated the development of new treatment approaches to parkinsonian, but has recently been criticized on the basis of new anatomical and biochemical data. In particular, the role of altered activity in GPe in parkinsonism has been challenged, and, related to this, the view that STN activity is increased in parkinsonism due to release from inhibition via GPe efferents has come under attack. Alternative mechanisms that were proposed to explain increased STN activity include increased glutamateric excitation of STN via efferents from cortex, thalamus or midbrain and reduced inhibition via mesencephalic dopaminergic inputs. The proposed experiments address these issues in normal and parkinsonian Rhesus monkeys. Microdialysis measurements of changes in transmitter levels will be used to assess changes in activity along GPe efferents, will be correlated with changes in discharge characteristics of neurons in GPe, and with changes in the activity of the GABA synthesizing enzyme, GAD/67, in the STN (S.A.1.). Behavioral consequences of GPe inactivation will be explored with injections of the GABA receptor agonist muscimol into GPe (S.A.2). The cause(s) for increased discharge along the STN-GPi pathway will be assessed with experiments measuring changes in glutamate levels in GPi in response to pharmacologic manipulation of dopaminergic, GABAergic and glutamatergic transmission in the STN (S.A.3). Finally, the hypothesis that parkinsonism-induced changes in the activity of basal ganglia pathways can be explained by striatal dopamine depletion will be tested with biochemical and behavioral experiments in which dopaminergic transmission in the striatum is transiently interrupted by intrastriatal injections of the dopamine antagonist haloperidol in normal animals, or restored by similar injections of the dopamine receptor agonist quinpirole in parkinsonian monkeys (S.A. 4). These experiments will better define the functional importance of changes in activity along the pathways connecting the basal ganglial nuclei in Parkinson's disease. This information is essential for the future development of rational pharmacological and neurosurgical treatments of parkinsonism.
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