There is increasing evidence on a molecular level that estrogen (EST) has significant effects on a variety of neuronal and receptor-mediated mechanisms that may convey direct cognitive and behavioral benefit and provide trophic support for neuronal systems. EST has a substantial interactive role in the expression and activity of Nerve Growth Factor (NGF) and its receptors, thereby directly producing neuroprotective and trophic effects. These effects can be manifest after short-term changes in EST levels. EST appears to also have signal-transduction modulating properties on a variety of neuronal systems. These effects are focused particularly on cholinergic neurons of the basal forebrain. These neurons have critical relevance for the development of age-related cognitive and behavioral changes as well as the symptoms of dementing disorders. Changes in EST levels after surgical and natural menopause are associated with negative changes in cognitive and behavioral functioning and these changes are preventable by EST administration. In addition, preliminary studies have shown positive effects of HRT on cognitive functioning in women with Alzheimer's disease. The primary goal of this project is to test the hypothesis that intermediate-term administration of estrogen (EST) to normal young and older post-menopausal women will quantitatively change the behavioral and cognitive responses to pharmacological challenge agents that directly interact with central cholinergic receptors. Young post-menopausal women (50-60) and older post-menopausal women (75+) will be blindly placed on EST and placebo patches for 3 months. They will then be challenged with 2 cholinergic antagonists (scopolamine and mecamylamine) and 2 agonists (nicotine and physostigmine) and their behavioral and cognitive responses measured. These results will have direct implications for the use of EST in post-menopausal women for the preservation of brain function as well as demonstrate the feasibility of this model for the clinical testing of other potential neuroprotective/neurotrophic substances for late-life mental disorders. To date we have screened 21 women and enrolled 18 subjects in the study of a required total of 30 subjects. We have had some initial difficulty with our dose regimen for scopolamine. Our initial dose calculations were based on previously published recommendations for scopolamine administration for the purposes of producing mild cognitive impairment. However the doses produced more severe cognitive impairment than we anticipated. We have adjusted our dose downward and are no longer experiencing any significant difficulties. We have been able to produce mild and reversible cognitive impairment sufficient for the purposes of the study. We are continuing to recruit and enroll subjects which has taken somewhat longer than we were initially estimating. Otherwise, the study is proceeding without difficulty.
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