SELECTIVE ESTROGEN RECEPTOR MODULATORS AND COGNITION

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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. Estradiol (E2) replacement therapy (ERT) is prescribed to hypoestrogenic women to protect against osteoporosis, cardiovascular disease, sexual dysfunction, mood disorders and cognitive impairments associated with ovariectomy or menopause. However, ERT increases risk of developing breast or uterine cancer. Selective estrogen receptor modulators (SERMs) have been developed to address these problems. SERMs mimic the positive effects of estrogens on specific tissues, yet have minimal proliferative effects on breast and endometrium. The effects of SERMS on cognition, however, are not known. We use the rhesus monkey model to determine the effects of the SERMs tamoxifen and raloxifene on cognitive function. Animals are tested on a battery of computerized memory and attentional tests that are sensitive to sex hormones or ovarian status, including Delayed Non-Matching to Sample, Delayed Recognition Span, and Visual Search tests. Because cognitive performance can be affected by motor ability, we expanded the scope of this project to include assessments of motor behavior. In an initial project we trained ovariectomized and gonadally intact monkeys to extract raisins from a Plexiglas board designed so that the optimal method of obtaining the raisins was to use both hands in a coordinated manner. Results indicated that ovarian status was without effect upon this task with both groups showing improvements in performance over time. We are continuing to study the influence of ovariectomy and hormonal treatments on motor function as well as upon the more complex battery of cognitive tasks. In addition, we have examined whether menstrual cyclicity in normal females influences resting brain activity as indicated by a PET imaging procedure that assesses glucose metabolism. Results indicate that several areas involved in the regulation of anxiety show changes across the cycle. Further studies will examine the effects of hormonal treatments on brain glucose metabolism in monkeys engaged in cognitive tasks.