Numerous investigations have now established that norepinephrine-containing cells, as well as cholinergic neurons, degenerate in the brains of patients with Alzheimer's Disease (AD); however, the role of norepinephrine loss in the cognitive deterioration which hallmarks this disease remains obscure. The propsoed research will examine the contributions of norepinephrine (NE) and dopamine (DA) loss in cortex to the cognitive deficits displayed by aged nonhuman primates with naturally-occurring catecholamine (CA) degeneration. Using behavioral, pharamacological, biochemical and receptor autoradiographic techniques, the relative roles of alpha and beta noradrenergic and dopaminergic systems in cognitive function will be examined by 1) comparing the effects of systemic and intro-cortical administration of selective CA agonists and antagonists on cognitive performance in aged monkeys, and 2) relating these findings to the pattern of CA degeneration in cortex. Special attention will be addressed to the alpha-2 noradrenergic system, as we recently found that the alpha-2 agonist, clonidine, ameliorates memory deficits in aged monkeys. We will determine whether clonidine's beneficial effects on memory result from direct actions in the areas of frontal association cortex known to subserve working memory functions, as well as defining the type of receptor where the drug acts. The mechanism of alpha-2 actions will be investigated by examining whether aplha-2 stimulation improves memory performance through an augmentaiton of cholinergic transmission in the frontal cortex as has been suggested in the rodent. As both NE and acetylcholine are lost in Alzheimer's Disease, these experiments also will have direct clinical relevance, suggesting and testing strategies for pharmacological treatment of age-related cognitive disorders in humans.
Showing the most recent 10 out of 36 publications
