Nicotinic cholinergic systems have been implicated in several important aspects of cognitive function (ex., attention, working memory, executive functioning) and are considered to be potential therapeutic agents for cognitive deficits in a variety of neurological and psychiatric disorders. However, the use of nicotine or subtype-selective neuronal nicotinic acetylcholine receptor (nAChR) agonists to treat cognitive dysfunctions characteristic of a progressive neurological disorder such as Parkinson's disease (PD) may pose particular challenges. It is still unknown which subtype(s) of nAChRs may be the most appropriate therapeutic target(s) and when during the course of the disease they may be most appropriate. The extent to which nAChR-mediated therapies for progressive disorders could be aiming at a 'moving target' (i.e., the therapeutic target may change as the disease progresses and nAChR subtype expression changes) is not known. Based on progress made during the current grant and new preliminary studies, we have generated the following specific aims: 1. Examine attention/executive functioning and memory functioning in """"""""early"""""""" parkinsonian (cognitive impairments and no motor symptoms), """"""""mild"""""""" parkinsonian (cognitive and mild motor deficits ) and """"""""moderate"""""""" parkinsonian (cognitive deficits and moderate motor deficits) monkeys. Hypothesis: Animals with progressively more severe parkinsonism will exhibit a broader range of cognitive impairments than those observed in early parkinsonian animals; 2. Assess the potential therapeutic effects of nicotine and subtype selective nAChR agonists on attention, executive functions and memory in monkeys with different degrees of parkinsonism. Hypothesis: Subtype selective nAChR agonists will have different effects on cognitive deficits in motor asymptomatic vs. symptomatic parkinsonian monkeys and results may further vary between animals with mild or moderate motor impairments; 3. Examine and compare changes nAChR gene and protein expression in """"""""early"""""""", """"""""mild"""""""", and """"""""moderate"""""""" parkinsonian monkeys. Hypothesis: nAChR subtype expression will be different in early vs. more progressed Parkinsonism and these differences may relate to the animal's scope of deficits as well as the relative responsiveness of deficits to nicotinic therapies. The proposed studies will extend our current work and further elucidate the role of nicotinic receptor subtypes in attention, memory and executive functioning. Information obtained from these studies will hopefully lead to more efficient design of nicotinic therapeutics for patients with a variety of cognitive disorders. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA013452-06
Application #
6969792
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Hoffman, Allison
Project Start
2000-07-01
Project End
2009-02-28
Budget Start
2006-05-01
Budget End
2007-02-28
Support Year
6
Fiscal Year
2006
Total Cost
$380,407
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Schneider, J S; Tinker, J P; Decamp, E (2010) Clonidine improves attentional and memory components of delayed response performance in a model of early Parkinsonism. Behav Brain Res 211:236-9
Decamp, E; Schneider, J S (2009) Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model. Brain Res 1262:109-14
Kulak, Jennifer M; Fan, Hong; Schneider, Jay S (2007) Beta2* and beta4* nicotinic acetylcholine receptor expression changes with progressive parkinsonism in non-human primates. Neurobiol Dis 27:312-9
Decamp, E; Schneider, J S (2006) Effects of nicotinic therapies on attention and executive functions in chronic low-dose MPTP-treated monkeys. Eur J Neurosci 24:2098-104
Kulak, Jennifer M; Carroll, F Ivy; Schneider, Jay S (2006) [125I]Iodomethyllycaconitine binds to alpha7 nicotinic acetylcholine receptors in monkey brain. Eur J Neurosci 23:2604-10
Decamp, E; Tinker, J P; Schneider, J S (2004) Attentional cueing reverses deficits in spatial working memory task performance in chronic low dose MPTP-treated monkeys. Behav Brain Res 152:259-62
Decamp, E; Schneider, J S (2004) Attention and executive function deficits in chronic low-dose MPTP-treated non-human primates. Eur J Neurosci 20:1371-8
Kulak, Jennifer M; Schneider, Jay S (2004) Differences in alpha7 nicotinic acetylcholine receptor binding in motor symptomatic and asymptomatic MPTP-treated monkeys. Brain Res 999:193-202
Schneider, J S; Tinker, J P; Menzaghi, F et al. (2003) The subtype-selective nicotinic acetylcholine receptor agonist SIB-1553A improves both attention and memory components of a spatial working memory task in chronic low dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys. J Pharmacol Exp Ther 306:401-6