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. ? ?
