This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary goal of this project is to use clinical and cognitive investigations to establish how estrogen and related compounds influence the functioning of the cholinergic systems of the human brain. The basic model that we will use throughout this proposal is to test the effects of gonadal steroids on a neurochemical """"""""lesion"""""""" model utilizing cholinergic antagonist drugs. This approach simulates the effects of age- or disease-related neuroreceptor and/or neuronal loss by temporarily blocking pre- and postsynaptic muscarinic and nicotinic cholinergic receptors. This model reliably produces mild and quantifiable but rapidly reversible cognitive impairment and has proved valuable in understanding the role of the cholinergic system and its loss on human cognitive functioning. We have utilized this model successfully to establish the effects of the loss of muscarinic and nicotinic cholinergic receptors in aging and neurodegenerative disorders. We have now extended this model to examine the effects of estrogen replacement on cholinergic function and cognitive performance in normal aging. Hypotheses: 1. Chronic administration of E2 over three months will produce significantly greater enhancement of cholinergic function (potentially through a trophic mechanism) than acutely administered E2 (e.g. through a pharmacologic mechanism). This will be manifested by blunting the performance-impairing effects of the cholinergic antagonists scopolamine (muscarinic) and mecamylamine (nicotinic) on attention, motor speed, verbal learning and memory. 2. E2 administered alone for 3 months will blunt the negative cognitive and performance effects of muscarinic and nicotinic cholinergic antagonist drugs, to a significantly greater degree than the combination of E2 plus Progesterone (PRO). These effects will be manifested on tasks of visuo-spatial learning and memory, motor speed, and verbal working memory. 3. The estrogen antagonist tamoxifen will enhance the cognition-impairing effects of cholinergic antagonists on tasks of visuo-spatial learning and memory, motor speed, and verbal working memory secondary to negative effects on cholinergic system integrity in the central nervous system.
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