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Vol. 75, No. 1, 2002
Issue release date: January 2002
Neuroendocrinology 2002;75:24–33
(DOI:10.1159/000048218)

Selective Estrogen Receptor Modulator Effects in the Rat Brain

Zhou W. · Koldzic-Zivanovic N. · Clarke C.H. · de Beun R. · Wassermann K. · Bury P.S. · Cunningham K.A. · Thomas M.L.
aDepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Tex., USA; Departments of bPharmacological Research 2, and cMedicinal Chemistry Research 3, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark

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Abstract

The effects in the brain of selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene have not yet been fully elucidated. Based upon the hypothesis that serotonin (5-HT)-steroid hormone interactions are important in mood regulation, we have compared six SERMs (tamoxifen, raloxifene, levormeloxifene, NNC 45-0781, NNC 45-0320, NNC 45-1506) with 17β-estradiol (E2) in terms of their ability to regulate mRNA levels of estrogen receptor (ER)α, ERβ, 5-HT1A receptor, and 5-HT reuptake transporter (SERT) in the midbrain, amygdala, and hypothalamus of ovariectomized (OVX) rats. Female rats (n = 6/group, 8 groups total) were OVX and allowed to recover for 2 weeks. During the third post-OVX week, rats were injected subcutaneously with E2 (0.1 mg/kg) or one of the SERMs (5 mg/kg) once per day for 7 days. Twenty-four hours after the last injection, tissue was collected for the determination of mRNA levels by ribonuclease protection assay (RPA). E2 treatment significantly decreased mRNA levels for ERα, ERβ, and SERT in midbrain and ERα in hypothalamus. Tamoxifen increased ERβ mRNA levels in hypothalamus, while raloxifene increased ERβ mRNA levels in amygdala. NNC 45-0320 decreased ERα mRNA in hypothalamus and decreased ERβ mRNA in amygdala. These results suggest that while SERMs are not full estrogen receptor agonists in the brain, the agonist/antagonist profiles for individual SERMs may differ among brain areas. This raises the possibility of developing new SERMs for selective functions in specific brain areas.



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