Our overall aim is to elucidate the mechanisms that underlie L-dopa-induced dyskinesias (LIDs) and to develop anti-dyskinetic strategies, with a focus on the nicotinic cholinergic system. L-dopa therapy is the gold standard for Parkinson's disease treatment. However, its use is associated with movement abnormalities, such as dyskinesias that may be as debilitating as the disease itself. Few treatments are available for LIDs, possibly because the mechanisms responsible for their development are still uncertain. Although extensive studies have implicated numerous neurotransmitters, the cholinergic system has received little attention to date. This is somewhat surprising given the overlapping network of dopaminergic terminals and cholinergic interneurons in the striatum, and the well-known ability of nicotinic receptors to regulate striatal dopamine release. With this in mind, we hypothesized that the nicotinic cholinergic system plays a role in LIDs, and initiated experiments in which nicotine and L-dopa were administered to parkinsonian monkeys. Our preliminary data demonstrate that nicotine consistently reduced peak and total LIDs (~50%) in parkinsonian monkeys. In addition, a crossover study subsequently showed that nicotine treatment also reduced LIDs in monkeys that had previously been given L-dopa. There was no decline in the antiparkinsonian action of L-dopa. We plan to extend these novel behavioral findings, as well as investigate the mechanisms responsible for the nicotine-induced reduction of LIDs through the following specific aims. First, we will identify the nicotine-dosing regimen that most effectively reduces LIDs. To approach this, we will test the effect of nicotine given at the same time and also after L-dopa administration, and determine the dose and time dependency of the nicotine-induced decline in LIDs. Second, we will identify the nicotinic receptor subtypes associated with the nicotine-induced decrease in dyskinesias. This work will provide a basis for the studies in Aim 3 to test the effect of nAChR subtype agonists for their antidyskinetic properties. Lastly, we will study the molecular and cellular mechanisms by which nicotine reduces dyskinesias. Treatment with nicotine, or select nicotinic agonists, represents a novel approach to reduce dyskinesias and could lead to the development of new strategies to attenuate this debilitating complication of L-dopa treatment in patients with Parkinson's disease.

Public Health Relevance

Our data show that nicotine administration reduces L-dopa induced dyskinesias in parkinsonian monkeys. The objective of this proposal is to evaluate the optimal mode of administration, to determine the nicotinic receptor subtypes and to understand the mechanisms through which nicotine exerts its antidyskinetic action. These studies have the potential to open up a new research direction for the treatment of dyskinesias in Parkinson's disease using drugs targeted to the nicotinic cholinergic system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059910-04
Application #
8324277
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sieber, Beth-Anne
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$790,548
Indirect Cost
$348,228
Name
Sri International
Department
Type
DUNS #
009232752
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A et al. (2016) Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia. Exp Neurol 286:32-39
Bordia, Tanuja; Perez, Xiomara A; Heiss, Jaime E et al. (2016) Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias. Neurobiol Dis 91:47-58
Shariff, Masroor; Quik, Maryka; Holgate, Joan et al. (2016) Neuronal Nicotinic Acetylcholine Receptor Modulators Reduce Sugar Intake. PLoS One 11:e0150270
Quik, Maryka; Zhang, Danhui; McGregor, Matthew et al. (2015) Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease. Biochem Pharmacol 97:399-407
Bordia, Tanuja; McGregor, Matthew; Papke, Roger L et al. (2015) The α7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions. Exp Neurol 263:277-84
Bordia, T; McGregor, M; McIntosh, J M et al. (2015) Evidence for a role for α6(∗) nAChRs in l-dopa-induced dyskinesias using Parkinsonian α6(∗) nAChR gain-of-function mice. Neuroscience 295:187-97
Zhang, Danhui; McGregor, Matthew; Bordia, Tanuja et al. (2015) α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage. Mov Disord 30:1901-11
Quik, Maryka; Bordia, Tanuja; Zhang, Danhui et al. (2015) Nicotine and Nicotinic Receptor Drugs: Potential for Parkinson's Disease and Drug-Induced Movement Disorders. Int Rev Neurobiol 124:247-71
Zhang, Danhui; Bordia, Tanuja; McGregor, Matthew et al. (2014) ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease. Mov Disord 29:508-17
Quik, Maryka; Zhang, Danhui; Perez, Xiomara A et al. (2014) Role for the nicotinic cholinergic system in movement disorders; therapeutic implications. Pharmacol Ther 144:50-9

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