Nicotinic cholinergic systems are involved in several important aspects of cognitive function including attention, memory and learning. However, there are still significant gaps in our knowledge of nicotine effects on cognition. This is particularly apparent in our understanding of the role of nicotine and nicotinic acetylcholine receptors (nAChRs) in the cognitive deficits associated with Parkinson's disease (PD). Since neither attention nor memory is a unitary process, they must be studied with various tasks that assess distinct attentional components as well as different aspects of memory. The research proposed in this application has the following specific aims: 1) Examine the effects of chronic low dose MPTP exposure on different components of attention (attention set shifting ability, focused (selective) attention, visuospatial attention shifting, sustained attention, distractibility) and memory (spatial working memory, nonspatial working memory, associative memory, visual recognition memory) in non-human primates. We hypothesize that chronic low dose MPTP-treated monkeys, a model for """"""""early"""""""" Parkinsonism, will display specific attention and memory deficits as a result of their specific neurochemical lesion. Specific pathologic and neurochemical changes in the brains of these animals should result in distinct patterns of cognitive deficits; 2) Assess the potential therapeutic effects of nicotine and sub-type selective nAChR agonists (ex., selective a4b2, a4b4 and a7) on attention and memory dysfunctions described under Specific Aim 1. We hypothesize that nicotine and different subtype selective nAChR agonists with different pharmacological profiles will have different effects on distinct components of attention and memory in chronic low dose MPTP-treated monkeys. Results from these studies will indicate which components of Parkinson-related attentional and memory deficits are responsive to specific mcotinic therapies and suggest possible new treatment strategies for cognitive deficits associated with Parkinson's disease; 3) Examine changes in gene expression and autoradiographic distribution of different nAChR subtypes in cortical and subcortical brain regions in our Parkinson model. We hypothesize that differences in regional expression of distinct nAChR subtypes in Parkinsonism will be related to the different types of cognitive impairments observed in these animals. These studies will provide important new data on nicotinic receptor distribution and gene expression in non-human primates. The proposed studies will be the first to provide a detailed examination of the scope of the attention and memory deficits associated with Parkinsonism in non-human primates, relate these findings to alterations in nAChR subtype expression and distribution and test potential ameliorative therapies based on selective pharmacological stimulation of nAChR subtypes. These studies should enhance our understanding of nicotinic acetylcholine involvement in cognition in non-human primates, whose behavioral repertoire resembles that generated by the human neurobehavioral system more than any other laboratory animal except higher apes, and lead to new therapies for cognitive dysfunctions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA013452-01A1
Application #
6326207
Study Section
Special Emphasis Panel (ZRG1-IFCN-7 (01))
Program Officer
Hoffman, Allison
Project Start
2001-04-20
Project End
2006-03-31
Budget Start
2001-04-20
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$354,417
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
061197161
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