In addition to maintaining bone density and cardiovascular health in women, estradiol (E2) also normalizes behavioral systems related to mood, sexuality, and adaptability. Although (E2) replacement prevents bone loss and reduces the risk of cardiovascular disease in hypoestrogenic women, such treatments may adversely affect the breast and uterus, despite co-treatment with progestins. Consequently, non-steroidal estrogens have been developed with specific targeted effects as E2 agonists in some tissues and antagonists in others. Since these tissue specific actions are likely mediated through subtypes of the estrogen receptor, the compounds are described as selective estrogen receptor modulators (SERMs). Despite their well-documented efficacy in peripheral target tissues, it is not known whether these SERMs act as E2 agonists or antagonists within the CNS regulating neurochemical mechanisms subserving complex social behavior. This project will determine if the SERMs, tamoxifen and raloxifene, are E2 agonists or antagonists in the neuroendocrine regulation of behavior in female rhesus monkeys. Using ovariectomized females, each of the Specific Aims will test the hypothesis that SERMs, in the absence of E2, act as agonists whereas, in the presence of E2, antagonistic effects will be observed.
Specific Aim 1 will determine if SERMs mimic E2 and increase affiliative behavior mediated by increased endogenous serotonergic (5HT) activity and whether these antagonize endogenous E2, diminishing 5HT activity and increase aggressiveness.
Specific Aim 2 will determine if SERMs absent E2 induce female sexual motivation and coordinate gonadotropin synthesis and secretion and whether these antagonize endogenous E2, blocking the induction of sexual motivation and regulation of gondadotropin release.
Specific Aim 3 will determine if SERMs act as agonists and attenuate the activation of the HPA axis in response to changes in the social environment, characterized by increased glucocorticoid negative feedback, a diminished response to corticotropin releasing hormone, and a decrease in the expression of stress-related gene products and whether they block endogenous E2, exacerbating the response to the HPA axis to social change. These data will provide not only a better understanding of the biology of SERMs but will also help clinicians and patients evaluate the efficacy of these compounds on behavioral health.
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