Our goal is to understand the effects of nigrostriatal damage and nicotine treatment on nicotinic receptor (nAChR) subtypes in the basal ganglia, and determine the relationship of any changes to neuroprotection. The rationale for such work is based, in part, on epidemiological studies showing that there is a decreased incidence of Parkinson's disease (PD) in smokers. This apparent neuroprotection may be due to nicotine in tobacco since nicotine protects against nigrostriatal damage in various experimental models. Nicotine exerts its effects by stimulating nAChRs. We hypothesize that nicotine-mediated protection against nigrostriatal damage occurs as a consequence of changes in nAChR subtypes. Our preliminary data show that there are differential changes in nAChRs subtypes and their function after MPTP treatment. In this proposal, we will test the effects of nicotine to modulate nAChRs, study its neuroprotective effects against nigrostriatal degeneration and investigate its mechanism(s) of action. This will be approached through the following Specific Aims. (1) We will test the hypothesis that nicotine administration influences nAChR expression and function in MPTP-treated mice. Although nicotine exposure is well-known to upregulate nAChRs in control animals, studies to determine its effects after nigrostriatal damage remain to be done. Next (2) we will test the hypothesis that nicotine-induced changes in nAChRs correlate with neuroprotection against nigrostriatal damage by measuring various markers of striatal dopaminergic function. These data will be correlated to changes in nAChRs to determine whether receptor alterations are linked to neuroprotection. (3) To determine whether specific nicotinic receptor subtypes are involved we will we will study whether nicotine protects against nigrostriatal damage in nAChR knockout mice. (4) Finally, experiments will be done to study the molecular mechanisms that mediate nicotine-induced neuroprotection. We will investigate the hypothesis that trophic factors such as basic fibroblast growth factor (bFGF) and brain derived neurotrophic factor (BDNF), as well as immune mediators such as interleukin-6, are involved. These studies will enhance our knowledge of the changes in nAChR expression and function with chronic nigrostriatal damage and nicotine treatment. This may allow for the design of neuroprotective strategies for PD, a disorder for which only symptomatic treatment is currently available.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047162-03
Application #
6995379
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Refolo, Lorenzo
Project Start
2004-01-15
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2006
Total Cost
$292,658
Indirect Cost
Name
Parkinson's Institute
Department
Type
DUNS #
614259935
City
Sunnyvale
State
CA
Country
United States
Zip Code
94085
Bordia, T; McGregor, M; McIntosh, J M et al. (2015) Evidence for a role for ?6(?) nAChRs in l-dopa-induced dyskinesias using Parkinsonian ?6(?) nAChR gain-of-function mice. Neuroscience 295:187-97
Bordia, Tanuja; McIntosh, J Michael; Quik, Maryka (2012) Nicotine reduces antipsychotic-induced orofacial dyskinesia in rats. J Pharmacol Exp Ther 340:612-9
Huang, Luping Z; Grady, Sharon R; Quik, Maryka (2011) Nicotine reduces L-DOPA-induced dyskinesias by acting at beta2* nicotinic receptors. J Pharmacol Exp Ther 338:932-41
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
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
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; Huang, Luping Z; Parameswaran, Neeraja et al. (2009) Multiple roles for nicotine in Parkinson's disease. Biochem Pharmacol 78:677-85
Perez, Xiomara A; O'Leary, Kathryn T; Parameswaran, Neeraja et al. (2009) Prominent role of alpha3/alpha6beta2* nAChRs in regulating evoked dopamine release in primate putamen: effect of long-term nicotine treatment. Mol Pharmacol 75:938-46
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

Showing the most recent 10 out of 27 publications