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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038917-02
Application #
6526383
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Parrott, Estella C
Project Start
2001-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$360,000
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Pazol, Karen; Northcutt, Katharine V; Patisaul, Heather B et al. (2009) Progesterone and medroxyprogesterone acetate differentially regulate alpha4 subunit expression of GABA(A) receptors in the CA1 hippocampus of female rats. Physiol Behav 97:58-61
Pazol, Karen; Northcutt, Katharine V; Wilson, Mark E et al. (2006) Medroxyprogesterone acetate acutely facilitates and sequentially inhibits sexual behavior in female rats. Horm Behav 49:105-13
Stroud, Fawn C; Appt, Susan E; Wilson, Mark E et al. (2006) Concentrations of isoflavones in macaques consuming standard laboratory monkey diet. J Am Assoc Lab Anim Sci 45:20-3
Wilson, Mark E; Fisher, Jeffrey; Brown, Juliet (2005) Chronic subcutaneous leptin infusion diminishes the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in female rhesus monkeys. Physiol Behav 84:449-58
Wilson, Mark E; Legendre, Ariadne; Pazol, Karen et al. (2005) Gonadal steroid modulation of the limbic-hypothalamic- pituitary-adrenal (LHPA) axis is influenced by social status in female rhesus monkeys. Endocrine 26:89-97
Mook, Deborah; Felger, Jennifer; Graves, Franklynn et al. (2005) Tamoxifen fails to affect central serotonergic tone but increases indices of anxiety in female rhesus macaques. Psychoneuroendocrinology 30:273-83
Patisaul, Heather B; Blum, Adele; Luskin, Jordan R et al. (2005) Dietary soy supplements produce opposite effects on anxiety in intact male and female rats in the elevated plus-maze. Behav Neurosci 119:587-94
Pazol, Karen; Kaplan, Jay R; Abbott, David et al. (2004) Practical measurement of total and bioavailable estradiol in female macaques. Clin Chim Acta 340:117-26
Patisaul, Heather B; Luskin, Jordan R; Wilson, Mark E (2004) A soy supplement and tamoxifen inhibit sexual behavior in female rats. Horm Behav 45:270-7
Wilson, M E; Mook, D; Graves, F et al. (2003) Tamoxifen is an estrogen antagonist on gonadotropin secretion and responsiveness of the hypothalamic-pituitary- adrenal axis in female monkeys. Endocrine 22:305-15

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