Parkinson's disease (PD) is characterized primarily by the loss of dopaminergic neurons in the substantia nigra that causes functional alterations of basal ganglia and typical motor symptoms. Dopamine replacement therapy has beneficial effects in the early stages, but as disease progresses, dopaminergic treatments fail to restore normal mobility and even produce additional motor abnormalities. Such altered responses to dopamine have been related to complex changes of dopamine D1 and D2 receptor-mediated mechanisms that regulate the striatal direct and indirect outputs. However, the activity of striatal projection neurons is also regulated by other neurotransmitter systems whose mechanisms may undergo plastic changes in the chronic evolution of PD. The glutamate system provides abundant cortical and thalamic excitatory inputs to the striatum, and several lines of evidence indicate that the increase of glutamatergic signaling may contribute to striatal dysfunction. This project is intended to study the role of dysregulation of striatal glutamatergic transmission in the pathophysiology of abnormal dopamine responses in chronic PD. The ultimate goal of the project is to identify targets for developing new treatments for the long-term management of PD. Specifically the project comprises three aims: 1. to study the relationship between glutamatergic hyperactivity and altered discharges of striatal projection neurons in chronically parkinsonian monkeys. We will use different classes of glutamate antagonists to block the striatal receptors locally with drug injections into the brain. 2. To examine the contribution of excessive glutamate release in the mechanisms of altered striatal discharges in the chronic primate model of PD. We will use cannabinoid CB1-acting drugs in striatal injections or infusions to study the effects on striatal neurons and motor responses to levodopa. 3. To study the role of striatal glutamatergic hyperactivity on changes in dopamine responses driven by the indirect striatal output pathway in the chronic primate model of PD. We will use glutamate antagonists in striatal infusions to examine the responses to selective dopamine agonists in external pallidal neurons. The project combines modern technologies in pharmacological and electrophysiological areas to study the underlying mechanisms of striatal dysfunction in chronic PD, and thus, it may contribute to developing new therapies for patients debilitated by the advanced disease.

Public Health Relevance

Current dopaminergic treatments of Parkinson's disease are associated with the development of motor complications and abnormal movements. These abnormal responses to dopaminergic drugs derive from functional changes in the basal ganglia, particularly in the dopamine-denervated striatum. This project is aimed at studying the mechanisms leading to progressive dysfunction of striatal neurons and movement abnormalities. Improved understanding of these mechanisms is critical to develop new treatments for motor complications and alleviate advanced parkinsonian patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Sieber, Beth-Anne
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Emory University
Schools of Medicine
United States
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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
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
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
Potts, Lisa F; Uthayathas, Subramaniam; Greven, Alexander C M et al. (2015) A new quantitative rating scale for dyskinesia in nonhuman primates. Behav Pharmacol 26:109-16
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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