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.
