Estradiol (E2) is essential for the health, estradiol (E2) also normalizes behavioral systems related to mood and sexuality. Although E2 replacement prevents bone loss and reduces the risk of cardiovascular disease in hypo- estrogenic women, such treatments may adversely affect the breast 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 (ER), 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 neuro-chemical 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 Specific Aims will test the hypothesis that SERMs, in the absence of E2, act as agonists whereas, in the presence of E2, are antagonists. Preliminary studies will determine the pharmacokinetics of the SERMs to set the parameters of the treatment protocol.
Specific Aim 1 will determine if SERMs mimic E2 and increase affiliative behavior mediated by increased central serotonergic (5HT) activity, assessed from concentrations of 5HT and its metabolite in cerebrospinal fluid, quantitative receptor autoradiography, and in situ hybridization for the 5HT re- uptake transporter. Subsequent studies will test the hypothesis that these SERMs antagonize endogenous E2, diminishing 5HT activity and increasing aggressiveness.
Specific Aim 2 will determine if SERMs, in the absence of E2, induce female sexual motivation and coordinate gonadotropin synthesis and secretion. Additional studies will test the hypothesis that these SERMs antagonize endogenous E2, blocking the induction of sexual motivation and regulation of gonadotropin synthesis and release. These data will provide not only a better understanding of the biology of SERMs but will also help clinicians and patients evaluate of these compounds on behavioral health.
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