This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project evaluates the pathophysiology of abnormal motor symptoms developed in the evolution of Parkinson's disease (PD). Dopamine replacement has beneficial effects in the early stages, but long-term therapy often fails to completely restore normal mobility, and may even produce additional motor abnormalities. Altered dopamine responses have been related to changes of dopamine receptor-mediated mechanisms that regulate the activity of striatal neurons. However, changes in other neurotransmitter systems, such as the glutamate system may also play a role. This project studies the role of altered glutamatergic transmission in the striatum in the pathophysiology of abnormal responses to levodopa. The goal of the project is to identify pharmacologic targets in the striatum that could be used to develop treatments for the long-term therapy of Parkinson's disease. The project comprises four aims: (1) To study the relationship between glutamatergic hyperactivity and altered discharges of striatal medium spiny neurons (MSNs) in chronically parkinsonian monkeys. Electrophysiologic recordings of MSNs are combined with local striatal injections of specific glutamate receptor antagonists (2) To examine the glutamate release to produce altered MSN discharges in chronic parkinsonism. We will reduce glutamatergic levels with cannabinoid CB1-acting drugs infused into the putamen of parkinsonian monkeys to study MSN firing changes and motor responses (3) To investigate the effects of gene knockdown of striatal NMDA receptor subunits on motor responses to chronic dopaminergic treatment. We will use viral vectors for siRNA-mediated gene silencing in rodents to reduce NMDA-receptor mediated transmission and determine its effects on motor behavior (4) To study the indirect striatal output drives that can develop in chronic PD and may be associated with abnormal motor responses to dopaminergic drugs. We will use dopamine agonists in putaminal infusions and record the MSN activity and neurons of the external segment of the globus pallidus in normal and parkinsonian monkeys.
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