Motor disturbances of Parkinson's disease are caused by a series of functional alterations in the basal ganglia that derive from dopamine denervation. The mechanisms underlying those functional alterations are not completely understood yet. Moreover, long-term levodopa therapy is usually associated with disabling motor complications, such as motor fluctuations and dyskinesias, whose pathophysiology also remains obscure. The long-term objective of this project is to elucidate the pathophysiologic mechanisms of abnormal motor behaviors in Parkinson's disease in view of developing new and specific therapeutic tools. Thus, this study is aimed: -firstly, to localize functional alterations in specific basal ganglia circuits; -secondly, to determine the glutamate regulation associated to an altered neuronal function; -finally, and based on the foregoing data, to explore new therapeutic approaches by interacting with the glutamatergic neurotransmission in a region-specific manner. Specifically this project comprises three aims: 1. To study the neuronal activity of individual basal ganglia regions by single cell recording in normal and various groups of parkinsonian monkeys (MPTP-treated primates) that exhibit different motor behaviors depending on treatment conditions (i.e.: parkinsonian state, its normalization, and drug-induced dyskinesias). 2. To study the glutamate receptor sensitivity in basal ganglia regions in relation to different motor conditions by comparing the binding of receptors across animal groups. 3. To study the glutamatergic blockade in restricted basal ganglia regions by determining its effects on neuronal activity and motor behavior. The research design includes techniques ranging from single- and multiple single- unit recording of neuronal activity, autoradiographic binding of receptors, to intracerebral administration of drugs in parkinsonian monkeys whose motor abnormalities closely resemble the human disease. This project proposes a novel approach to a comprehensive study of the abnormal motor function in Parkinson's disease. Thus, it will largely contribute to the rationale for new treatments that selectively target particular motor conditions. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045962-05
Application #
7385077
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Sieber, Beth-Anne
Project Start
2004-03-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$293,838
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Beck, Goichi; Maehara, Shunsuke; Chang, Phat Ly et al. (2018) A Selective Phosphodiesterase 10A Inhibitor Reduces L-Dopa-Induced Dyskinesias in Parkinsonian Monkeys. Mov Disord 33:805-814
Singh, Arun; Jenkins, Meagan A; Burke Jr, Kenneth J et al. (2018) Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates. Cell Rep 22:941-952
Chen, Guiqin; Nie, Shuke; Han, Chao et al. (2017) Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats. Front Neurosci 11:112
Singh, Arun; Mewes, Klaus; Gross, Robert E et al. (2016) Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease. Proc Natl Acad Sci U S A 113:9629-34
Masilamoni, Gunasingh J; Uthayathas, Subramanian; Koenig, Gerhard et al. (2016) Effects of a novel phosphodiesterase 10A inhibitor in non-human primates: A therapeutic approach for schizophrenia with improved side effect profile. Neuropharmacology 110:449-457
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Singh, Arun; Liang, Li; Kaneoke, Yoshiki et al. (2015) Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates. J Neurophysiol 113:1533-44
Singh, Arun; Gutekunst, Claire A; Uthayathas, Subramaniam et al. (2015) Effects of fibroblast transplantation into the internal pallidum on levodopa-induced dyskinesias in parkinsonian non-human primates. Neurosci Bull 31:705-13
Potts, Lisa F; Park, Eun S; Woo, Jong-Min et al. (2015) Dual ?-agonist/?-antagonist opioid receptor modulation reduces levodopa-induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease. Ann Neurol 77:930-41
Uthayathas, Subramaniam; Masilamoni, Gunasingh J; Shaffer, Christopher L et al. (2014) Phosphodiesterase 10A inhibitor MP-10 effects in primates: comparison with risperidone and mechanistic implications. Neuropharmacology 77:257-67

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