Selective estrogen receptor modulator effects in the rat brain.

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 17beta-estradiol (E(2)) in terms of their ability to regulate mRNA levels of estrogen receptor (ER)alpha, ER beta, 5-HT(1A) 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 E(2) (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). E(2) treatment significantly decreased mRNA levels for ER alpha, ER beta, and SERT in midbrain and ER alpha in hypothalamus. Tamoxifen increased ER beta mRNA levels in hypothalamus, while raloxifene increased ER beta mRNA levels in amygdala. NNC 45-0320 decreased ER alpha mRNA in hypothalamus and decreased ER beta 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. Copyright 2002 S. Karger AG, Basel