The catecholamines, dopamine and norepinephrine, decrease in the cortex of aged individuals, and norepinephrine is further depleted in patient with Alzheimer's Disease. The proposed research utilizes aged nonhuman primates as a model system to study how norepinephrine and dopamine loss contribute to the cognitive deficits which develop with advancing age. The research focuses on the principal sulcal region of the prefrontal cortex, as this cortex is especially vulnerable to the aging process, both in its loss of catecholamines and its ability to perform cognitive functions. Intracortical infusions directly into the principal sulcal cortex, as well as systemic administration of pharmacological agents will be used to observe how catecholamines act at specific receptors to affect the working memory abilities of the prefrontal cortex in the aged primate. Dopamine's effects at D1 and D2 receptors will be explored using the newly available D1 and D2-selective agents, and interactions between these receptors will be examined through combined drug treatment. Norepinephrine's actions as alpha-1 and beta receptors will be compared to its beneficial influence at alpha-2 receptors in the prefrontal cortex, and we will explore the possibility that alpha- 2 and beta receptor stimulation interact to elevate cAMP levels in prefrontal cortex and produce long lasting improvement in working memory abilities. Finally, we will more fully characterize the cognitive effects and mechanism of action of guanfacine, and alpha- 2 agonist which we've found to improve memory without hypotensive or sedative side effects. On the basis of our findings in aged monkeys, guanfacine currently is being tested in patients with Benign Senescence, Alzheimer's Disease and Korsakoff's amnesia, thus demonstrating the immediate clinical relevance of this project.
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