Our goal is to determine the role of nicotinic receptor subtypes in the basal ganglia with the long-term objective of developing novel therapeutic strategies for Parkinson's disease. The rationale for this work is based on studies showing that nicotine administration improves locomotor deficits after a nigrostriatal lesion and, furthermore, that nicotine or smoking results in an apparent protective effect against nigrostriatal damage in rodents and in Parkinson's disease. However, multiple nicotinic receptors are activated by nicotine to result in beneficial but also side effects in both the peripheral and central nervous system. We hypothesize that specific nicotinic receptor populations in the brain are involved based on work demonstrating that the distinct subtypes have unique localization and molecular functions. We will approach these studies through four specific aims. As a crucial first step, we will identify the regional and cellular localization of nicotinic receptor subtypes in basal ganglia and determine the changes in receptor subtypes after nigrostriatal degeneration. This will be done using three different approaches including in situ hybridization, receptor autoradiography and immunocytochemistry and form the basis of Specific Aims 1 and 2. We will then initiate studies to assess the nicotinic receptor subtypes involved in striatal function as described in Specific Aim 3, followed by behavioral studies (Specific Aim 4) to determine the ability of nicotinic agonists to reverse parkinsonism. This work should increase our understanding of the role of different nicotinic receptor subtypes in basal ganglia function. ? ? In summary, the proposed work should provide new insight concerning alterations in nicotinic receptor subtypes after nigrostriatal damage and nicotinic agonist treatment. These data together with the results of the behavioral studies may form a basis for the use of nicotinic drugs in the treatment of Parkinson's disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042091-03
Application #
6876627
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Refolo, Lorenzo
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$335,801
Indirect Cost
Name
Parkinson's Institute
Department
Type
DUNS #
614259935
City
Sunnyvale
State
CA
Country
United States
Zip Code
94085
Quik, Maryka; Perez, Xiomara A; Grady, Sharon R (2011) Role of ýý6 nicotinic receptors in CNS dopaminergic function: relevance to addiction and neurological disorders. Biochem Pharmacol 82:873-82
Pérez, Xiomara A; Quik, Maryka (2011) Focus on ?4?2* and ?6?2* nAChRs for Parkinson's Disease Therapeutics. Mol Cell Pharmacol 3:1-6
Quik, Maryka; Wonnacott, Susan (2011) ?6?2* and ?4?2* nicotinic acetylcholine receptors as drug targets for Parkinson's disease. Pharmacol Rev 63:938-66
Quik, Maryka; Bordia, Tanuja; Huang, Luping et al. (2011) Targeting nicotinic receptors for Parkinson's disease therapy. CNS Neurol Disord Drug Targets 10:651-8
Huang, Luping Z; Campos, Carla; Ly, Jason et al. (2011) Nicotinic receptor agonists decrease L-dopa-induced dyskinesias most effectively in partially lesioned parkinsonian rats. Neuropharmacology 60:861-8
Perez, Xiomara A; Bordia, Tanuja; McIntosh, J Michael et al. (2010) ?6ß2* and ?4ß2* nicotinic receptors both regulate dopamine signaling with increased nigrostriatal damage: relevance to Parkinson's disease. Mol Pharmacol 78:971-80
Bordia, Tanuja; Campos, Carla; McIntosh, J Michael et al. (2010) Nicotinic receptor-mediated reduction in L-DOPA-induced dyskinesias may occur via desensitization. J Pharmacol Exp Ther 333:929-38
Quik, Maryka; Campos, Carla; Parameswaran, Neeraja et al. (2010) Chronic nicotine treatment increases nAChRs and microglial expression in monkey substantia nigra after nigrostriatal damage. J Mol Neurosci 40:105-13
Huang, Luping Z; Parameswaran, Neeraja; Bordia, Tanuja et al. (2009) Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys. J Neurochem 109:826-37
Quik, Maryka; Huang, Luping Z; Parameswaran, Neeraja et al. (2009) Multiple roles for nicotine in Parkinson's disease. Biochem Pharmacol 78:677-85

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